Velcade

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Velcade

Classes

Small Molecule Antineoplastic Proteosome Inhibitors

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Low
Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
Nonvesicant

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
The bortezomib reconstituted vial concentration or syringe concentration differs based on route; use caution when calculating the volume to be administered.
The drug quantity contained in one vial may exceed the usual dose required; use caution when calculating the dose to prevent overdose.

Intravenous Administration

Use care in product selection and preparation; some products require reconstitution or further dilution before intravenous (IV) administration. Bortezomib for injection for IV use is available as 1-mg, 2.5-mg, and 3.5-mg lyophilized powder vials; 1-mg/mL solution vials (no dilution required); and also 2.5-mg/mL and 3.5-mg/1.4 mL solution vials (dilution required).
Refer to the specific manufacturer package insert for detailed instructions regarding reconstitution, storage, and administration for the product chosen.
 
Reconstitution of Lyophilized Powder Vials
Add the appropriate amount of 0.9% Sodium Chloride for Injection to the lyophilized powder vial for a final concentration of 1 mg/mL:
1-mg vial: add 1 mL 0.9% Sodium Chloride for Injection.
2.5-mg vial: add 2.5 mL 0.9% Sodium Chloride for Injection.
3.5-mg vial: add 3.5 mL 0.9% Sodium Chloride for Injection.
 
Preparation of Solution Vials Requiring Dilution
Add the appropriate amount of 0.9% Sodium Chloride for Injection to the injection solution vial for a final concentration of 1 mg/mL:
2.5 mg/mL solution vial: add 1.5 mL 0.9% Sodium Chloride for Injection.
3.5 mg/1.4 mL solution vial: add 2.1 mL 0.9% Sodium Chloride for Injection.
 
Preparation of Syringe:
Withdraw the bortezomib dose from solution vials requiring dilution using a polypropylene syringe.
Determine the volume of reconstituted bortezomib to be drawn into a syringe by multiplying the desired dose in mg/m2 by the patient's BSA and dividing the result by the bortezomib concentration (1 mg/mL); discard any unused drug remaining in the vial.
Place a sticker that indicates IV administration on the syringe.
Storage: Store the reconstituted vial or prepared syringe at 25 degrees C (77 degrees F); administer within 8 hours of preparation. Total storage time for the reconstituted or diluted material, whether in a vial or syringe, must not exceed 8 hours when exposed to normal indoor lighting.
 
Administration of Intravenous (IV) Injection:
Inject the 1 mg/mL final concentration solution as an IV bolus over 3 to 5 seconds.

Subcutaneous Administration

Use care in product selection and preparation. Bortezomib injection for subcutaneous use is available as 1-mg, 2.5-mg, and 3.5-mg lyophilized powder vials.
Refer to the specific manufacturer package insert for detailed instructions regarding reconstitution, storage, and administration for the product chosen.
 
Reconstitution of Lyophilized Powder Vials
Add the appropriate amount of 0.9% Sodium Chloride for Injection to the lyophilized vial for a final concentration of 2.5 mg/mL:
1-mg vial: add 0.4 mL 0.9% Sodium Chloride for Injection.
2.5-mg vial: add 1 mL 0.9% Sodium Chloride for Injection.
3.5-mg vial: add 1.4 mL 0.9% sodium chloride for injection.
 
Preparation of Syringe:
Determine the volume of reconstituted bortezomib to be drawn into a syringe by multiplying the desired dose in mg/m2 by the patient's BSA and dividing the result by the bortezomib concentration (2.5 mg/mL); discard any unused drug remaining in the vial.
If a local injection-site reaction occurs with the 2.5 mg/mL solution, consider using a less concentrated solution of 1 mg/mL or switching to the IV route.
Place a sticker that indicates subcutaneous administration on the syringe.
Storage: Store the reconstituted vial or prepared syringe at 20 to 25 degrees C (68 to 77 degrees F); administer within 8 hours of reconstitution.
 
Subcutaneous injection:
Inject subcutaneously in the thigh or abdomen; do not inject into a site that is tender, bruised, erythematous, or indurated.
Rotate injection sites with each injection; new sites should be at least 1 inch from an old site.

Adverse Reactions
Severe

neutropenia / Delayed / 3.0-83.0
thrombocytopenia / Delayed / 6.0-57.0
leukopenia / Delayed / 21.0-43.0
lymphopenia / Delayed / 19.0-25.0
peripheral neuropathy / Delayed / 8.0-13.0
anemia / Delayed / 1.0-13.0
fatigue / Early / 6.0-10.0
diarrhea / Early / 5.0-9.0
infection / Delayed / 5.0-5.0
asthenia / Delayed / 3.0-5.0
vomiting / Early / 0-4.0
nausea / Early / 0-3.0
weakness / Early / 2.0-3.0
dizziness / Early / 0-3.0
orthostatic hypotension / Delayed / 0-3.0
hypotension / Rapid / 0-3.0
rash / Early / 0-3.0
fever / Early / 0-3.0
constipation / Delayed / 0-2.0
anorexia / Delayed / 0-2.0
paresthesias / Delayed / 1.0-2.0
stomatitis / Delayed / 1.0-1.0
abdominal pain / Early / 0-1.0
hypoesthesia / Delayed / 1.0-1.0
headache / Early / 0-1.0
bleeding / Early / 1.0-1.0
cardiac tamponade / Delayed / 0-1.0
heart failure / Delayed / 0-1.0
hypertension / Early / 0-1.0
toxic epidermal necrolysis / Delayed / 0-1.0
Stevens-Johnson syndrome / Delayed / 0-1.0
alopecia / Delayed / 0-1.0
hyperglycemia / Delayed / 0-1.0
pulmonary edema / Early / 0-1.0
insomnia / Early / 0-1.0
peripheral edema / Delayed / 0-1.0
GI perforation / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
ileus / Delayed / Incidence not known
hematemesis / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
Guillain-Barre syndrome / Delayed / Incidence not known
leukoencephalopathy / Delayed / Incidence not known
cranial nerve palsies / Delayed / Incidence not known
stroke / Early / Incidence not known
muscle paralysis / Delayed / Incidence not known
seizures / Delayed / Incidence not known
coma / Early / Incidence not known
GI bleeding / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
intracranial bleeding / Delayed / Incidence not known
atrial flutter / Early / Incidence not known
bradycardia / Rapid / Incidence not known
pericarditis / Delayed / Incidence not known
atrial fibrillation / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
torsade de pointes / Rapid / Incidence not known
pericardial effusion / Delayed / Incidence not known
AV block / Early / Incidence not known
cardiac arrest / Early / Incidence not known
ventricular tachycardia / Early / Incidence not known
vasculitis / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
pulmonary hypertension / Delayed / Incidence not known
pleural effusion / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known
hyperkalemia / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
suicidal ideation / Delayed / Incidence not known
hearing loss / Delayed / Incidence not known
thrombotic microangiopathy / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
hemolytic-uremic syndrome / Delayed / Incidence not known

Moderate

bone pain / Delayed / 11.0-16.0
QT prolongation / Rapid / 0-1.0
encephalopathy / Delayed / 0-1.0
melena / Delayed / Incidence not known
gastritis / Delayed / Incidence not known
ascites / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
colitis / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
dysarthria / Delayed / Incidence not known
subdural hematoma / Early / Incidence not known
angina / Early / Incidence not known
hematoma / Early / Incidence not known
erythema / Early / Incidence not known
phlebitis / Rapid / Incidence not known
hypoglycemia / Early / Incidence not known
candidiasis / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hypoxia / Early / Incidence not known
pneumonitis / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
dehydration / Delayed / Incidence not known
hypernatremia / Delayed / Incidence not known
hypokalemia / Delayed / Incidence not known
hyperuricemia / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
urinary incontinence / Early / Incidence not known
bladder spasm / Early / Incidence not known
urinary retention / Early / Incidence not known
cystitis / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
confusion / Early / Incidence not known
psychosis / Early / Incidence not known
blurred vision / Early / Incidence not known
ocular infection / Delayed / Incidence not known
edema / Delayed / Incidence not known
blepharitis / Early / Incidence not known

Mild

arthralgia / Delayed / 11.0-17.0
back pain / Delayed / 13.0-17.0
pruritus / Rapid / 10.0-10.0
syncope / Early / 0-1.0
dysgeusia / Early / Incidence not known
gastroesophageal reflux / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
dyspepsia / Early / Incidence not known
skin irritation / Early / Incidence not known
injection site reaction / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
myalgia / Early / Incidence not known
epistaxis / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
weight loss / Delayed / Incidence not known
agitation / Early / Incidence not known
anxiety / Delayed / Incidence not known
malaise / Early / Incidence not known
diplopia / Early / Incidence not known
ocular irritation / Rapid / Incidence not known
vertigo / Early / Incidence not known
chills / Rapid / Incidence not known
chalazion (meibomian cyst) / Delayed / Incidence not known

Common Brand Names

Velcade

Dea Class

Rx

Description

A proteasome inhibitor; administered intravenously or subcutaneously
Used for the treatment of multiple myeloma and mantle cell lymphoma
Patients with pre-existing severe neuropathy should receive bortezomib only after careful risk-benefit assessment

Dosage And Indications
For the treatment of multiple myeloma.
NOTE: The FDA has designated bortezomib as an orphan drug for this indication.
For previously untreated multiple myeloma, in combination with melphalan and prednisone. Intravenous dosage Adults

Treatment is administered for nine 6-week cycles. In cycles 1 to 4, 1.3 mg/m2 IV on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21), then 1.3 mg/m2 IV on days 22, 25, 29, and 32 followed by a 10-day rest period (on days 33 to 42) in combination with melphalan (9 mg/m2 PO daily on days 1, 2, 3, and 4) and prednisone (60 mg/m2 on days 1, 2, 3, and 4); this 6-week cycle is considered 1 course. In cycles 5 to 9, bortezomib 1.3 mg/m2 IV over 3 to 5 seconds on days 1, 8, 22, and 29 in combination with melphalan (9 mg/m2 PO daily on days 1, 2, 3, and 4) and prednisone (60 mg/m2 PO daily on days 1, 2, 3, and 4); a 6-week cycle is considered 1 course. At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. At a median follow-up time of 16.3 months, the primary endpoint of median time to progression was significantly improved with bortezomib, melphalan, and prednisone (VMP) (median of 8 treatment cycles) compared with melphalan and prednisone (MP) alone (24 months vs. 16.6 months; hazard ratio [HR] = 0.48; p less than 0.001) in patients with previously untreated multiple myeloma who were transplant ineligible in a multinational, randomized, phase 3 trial (the VISTA trial; n = 682). The median overall survival (OS) time (secondary endpoint) was not reached in either study arm at this analysis; however, OS was significantly improved in the VMP arm (HR = 0.61; p = 0.0008). At a median follow-up time of 61 months, the median OS was significantly improved with VMP compared with MP alone (56.4 months vs. 43.1 months; HR = 0.695; p less than 0.001); 5-year OS rates were 46% and 34.4%, respectively.

Subcutaneous dosage Adults

Treatment is administered for nine 6-week cycles. In cycles 1 to 4, 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21), then 1.3 mg/m2 subcutaneously on days 22, 25, 29, and 32 followed by a 10-day rest period (on days 33 to 42) in combination with melphalan (9 mg/m2 PO daily on days 1, 2, 3, and 4) and prednisone (60 mg/m2 PO daily on days 1, 2, 3, and 4); this 6-week cycle is considered 1 course. In cycles 5 to 9, bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 22, and 29 in combination with melphalan (9 mg/m2 PO daily on days 1, 2, 3, and 4) and prednisone (60 mg/m2 PO daily on days 1, 2, 3, and 4); a 6-week cycle is considered 1 course. At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. At a median follow-up time of 16.3 months, the primary endpoint of median time to progression was significantly improved with bortezomib (IV), melphalan, and prednisone (VMP) (median of 8 treatment cycles) compared with melphalan and prednisone (MP) alone (24 months vs. 16.6 months; hazard ratio [HR] = 0.48; p less than 0.001) in patients with previously untreated multiple myeloma who were transplant ineligible in a multinational, randomized, phase 3 trial (the VISTA trial; n = 682). The median overall survival (OS) time (secondary endpoint) was not reached in either study arm at this analysis; however, OS was significantly improved in the VMP arm (HR = 0.61; p = 0.0008). At a median follow-up time of 61 months, the median OS was significantly improved with VMP compared with MP alone (56.4 months vs. 43.1 months; HR = 0.695; p less than 0.001); 5-year OS rates were 46% and 34.4%, respectively.

For the treatment of relapsed multiple myeloma. Intravenous dosage Adults

1.3 mg/m2 IV on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21); this 3-week cycle is considered 1 course. For extended therapy of more than 8 cycles, administer bortezomib 1.3 mg/m2 IV over 3 to 5 seconds on the standard 3-week cycle or on days 1, 8, 15, and 22 followed by a 13-day rest period (on days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. The primary endpoint of median time to progression (TTP) was significantly improved with IV bortezomib compared with high-dose dexamethasone (6.22 months vs. 3.49 months; hazard ratio [HR] = 0.55; p less than 0.001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, phase 3 trial (the APEX trial; n = 669). At 1 year of follow-up, the OS was significantly improved with bortezomib therapy (HR = 0.57; p = 0.001) despite 44% of patients with disease progression in the dexamethasone arm crossing over to the bortezomib arm. Due to favorable efficacy results at an interim analysis, all patients in the dexamethasone arm were offered bortezomib. At a median follow-up time of 22 months, the median OS was significantly improved with bortezomib compared with dexamethasone (29.8 months vs. 23.7 months; HR = 0.77; p less than 0.027); 1-year OS rates were 80% and 67%, respectively. More than 62% of patients in the dexamethasone arm had crossed over to the bortezomib arm at the time of this analysis. Treatment with single-agent IV bortezomib led to a median TTP of 7 months and a median OS of 17 months in patients with relapsed and refractory multiple myeloma who had received a median of 6 prior therapies (range, 2 to 15 therapies) in a single-arm, phase 2 trial (the SUMMIT trial; n = 202). Dexamethasone 20 mg PO on the day of and the day after bortezomib was permitted starting in cycle 2 in patients with disease progression or starting in cycle 4 in patients with stable disease.

Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21); this 3-week cycle is considered 1 course. For extended therapy of more than 8 cycles, administer bortezomib 1.3 mg/m2 subcutaneously on the standard 3-week cycle or on days 1, 8, 15, and 22 followed by a 13-day rest period (on days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. Subcutaneous administration of bortezomib resulted in noninferior efficacy and fewer grade 3 or higher adverse events compared with IV administration in patients with relapsed multiple myeloma in a randomized, phase 3 study (n = 222). Additionally, subcutaneous bortezomib was associated with significantly lower rates of peripheral neuropathy compared with IV administration. The primary endpoint of median time to progression (TTP) was significantly improved with IV bortezomib compared with high-dose dexamethasone (6.22 months vs. 3.49 months; hazard ratio [HR] = 0.55; p less than 0.001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, phase 3 trial (the APEX trial; n = 669). At 1 year of follow-up, the OS was significantly improved with bortezomib therapy (HR = 0.57; p = 0.001) despite 44% of patients with disease progression in the dexamethasone arm crossing over to the bortezomib arm. Due to favorable efficacy results at an interim analysis, all patients in the dexamethasone arm were offered bortezomib. At a median follow-up time of 22 months, the median OS was significantly improved with bortezomib compared with dexamethasone (29.8 months vs. 23.7 months; HR = 0.77; p less than 0.027); 1-year OS rates were 80% and 67%, respectively. More than 62% of patients in the dexamethasone arm had crossed over to the bortezomib arm at the time of this analysis. Treatment with single-agent IV bortezomib led to a median TTP of 7 months and a median OS of 17 months in patients with relapsed and refractory multiple myeloma who had received a median of 6 prior therapies (range, 2 to 15 therapies) in a single-arm, phase 2 trial (the SUMMIT trial; n = 202). Dexamethasone 20 mg PO on the day of and the day after bortezomib was permitted starting in cycle 2 in patients with disease progression or starting in cycle 4 in patients with stable disease.

For the treatment of relapsed or refractory multiple myeloma in patients who have received at least 1 prior therapy, in combination with doxorubicin liposomal†.
NOTE: Doxorubicin Liposomal is FDA approved in combination with bortezomib for the treatment of relapsed or refractory multiple myeloma in patients who have received at least 1 prior therapy besides bortezomib.
Intravenous dosage Adults

1.3 mg/m2 IV on days 1, 4 , 8, and 11 repeated every 3 weeks in combination with doxorubicin liposomal 30 mg/m2 IV over 1 hour on day 4 of each cycle; give doxorubicin liposomal after bortezomib on day 4. Administer up to 8 treatment cycles or until disease progression or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. At a planned interim analysis (median follow-up of 7.2 months), the primary endpoint of median time to progression was significantly improved with bortezomib plus pegylated liposomal doxorubicin (PLD) compared with bortezomib alone (9.3 months vs. 6.5 months; p less than 0.000004) in patients with relapsed or refractory multiple myeloma who had received at least 1 prior therapy in a multinational, randomized, phase 3 trial (n = 646). Overall survival was not significantly improved with bortezomib plus PLD compared with bortezomib alone (33 months vs. 31 months; HR = 0.96; 95% CI, 0.8 to 1.14) in the final survival analysis.

For newly diagnosed multiple myeloma as induction therapy prior to autologous stem-cell transplantation, in combination with dexamethasone†. Intravenous dosage Adults 65 years and younger

1.3 mg/m2 IV on days 1, 4, 8, and 11 plus dexamethasone 40 mg PO days 1, 2, 3, and 4 on all cycles and on days 9, 10, 11, and 12 on cycles 1 and 2 only repeated every 3 weeks for 4 cycles as induction therapy prior to autologous stem-cell transplantation has been evaluated in newly diagnosed multiple myeloma patients in randomized, phase 3 studies. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For newly diagnosed multiple myeloma as induction therapy prior to autologous stem-cell transplantation, in combination with thalidomide and dexamethasone†. Intravenous dosage Adults 65 years and younger

1.3 mg/m2 IV on days 1, 4, 8, and 11 plus thalidomide 100 mg PO daily for the first 14 days (cycle 1 only) then 200 mg PO daily thereafter and dexamethasone 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 (VTD regimen) repeated every 21 days for 3 cycles prior to a double (tandem) autologous stem-cell transplant (ASCT) was studied in a multicenter, randomized, phase 3 study. Patients randomized to induction therapy with VTD also received two 35-day consolidation cycles with VTD (bortezomib 1.3 mg/m2 IV on days 1, 8, 15, and 22 plus thalidomide 100 mg PO daily and dexamethasone 40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) following the second transplantation. Patients also received maintenance therapy with dexamethasone 40 mg PO on days 1, 2, 3, and 4 repeated every 28 days until relapse or disease progression. Additionally, bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 plus thalidomide 200 mg PO daily (dose escalation as follows in the first cycle: 50 mg/day on days 1 to 14, 100 mg/day on days 15 to 28) and dexamethasone 40 mg on days 1, 2, 3, and 4 and 9, 10, 11, and 12 repeated every 4 weeks for 6 cycles prior to an ASCT was studied in another randomized, phase 3 study. In this study, patients who received up to 3 years of maintenance therapy (starting 3 months after ASCT) with bortezomib (1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 3 months) plus thalidomide (100 mg/day) had significantly improved 2-year progression-free survival compared with thalidomide or interferon alfa-2b maintenance therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of relapsed multiple myeloma in patients who have previously responded to treatment with bortezomib (either alone or in combination) and have relapsed at least 6 months after completing prior bortezomib treatment. Intravenous dosage Adults

Begin treatment at the last tolerated bortezomib IV dose on days 1, 4, 8, and 11, either as a single agent or in combination with dexamethasone, every 3 weeks for a maximum of 8 cycles. Wait at least 72 hours between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. Patients who had relapsed or had progressive multiple myeloma at least 6 months after bortezomib therapy and who had at least a partial response (PR) to a bortezomib-containing regimen were re-treated with the last tolerated dose of bortezomib as a single agent or in combination with dexamethasone in a multinational, open-label, phase 2 trial (n = 126). The median time from prior bortezomib treatment was 13.9 months (range, 5 to 39 months) and patients had a median of 2 prior therapies (range, 1 to 7 therapies). After a median of 7 bortezomib re-treatment cycles (range, 1 to 8 cycles), the overall response rate (ORR) was 40% (complete response rate, 1%; PR rate, 39%). The ORR was 32% in patients re-treated with single-agent bortezomib (n = 34) and 42% in patients re-treated with bortezomib and dexamethasone (n = 92). The median duration of response was 6.5 months (range, 0.6 to 19.3 months).

Subcutaneous dosage Adults

Begin treatment at the last tolerated bortezomib subcutaneous dose on days 1, 4, 8, and 11, either as a single agent or in combination with dexamethasone, every 3 weeks for a maximum of 8 cycles. At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. Subcutaneous administration of bortezomib resulted in noninferior efficacy and fewer grade 3 or higher adverse events compared with IV administration in patients with relapsed multiple myeloma in a randomized, phase 3 study (n = 222). Additionally, subcutaneous bortezomib was associated with significantly lower rates of peripheral neuropathy compared with IV administration. Patients who had relapsed or had progressive multiple myeloma at least 6 months after bortezomib therapy and who had at least a partial response (PR) to a bortezomib-containing regimen were re-treated with the last tolerated dose of bortezomib as a single agent or in combination with dexamethasone in a multinational, open-label, phase 2 trial (n = 126). The median time from prior bortezomib treatment was 13.9 months (range, 5 to 39 months) and patients had a median of 2 prior therapies (range, 1 to 7 therapies). After a median of 7 bortezomib re-treatment cycles (range, 1 to 8 cycles), the overall response rate (ORR) was 40% (complete response rate, 1%; PR rate, 39%). The ORR was 32% in patients re-treated with single-agent bortezomib (n = 34) and 42% in patients re-treated with bortezomib and dexamethasone (n = 92). The median duration of response was 6.5 months (range, 0.6 to 19.3 months).

For the treatment of relapsed or refractory multiple myeloma, in combination with vorinostat†. Intravenous dosage Adults

1.3 mg/m2 IV days 1, 4, 8, and 11 in combination with vorinostat 400 mg orally once daily with food on days 1 to 14 repeated every 21 days was evaluated in relapsed or refractory multiple myeloma patients in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 637; VANTAGE 088 trial); 23.7% of patients received concurrent corticosteroids during the study period. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of multiple myeloma in patients who have received at least 2 prior therapies (including bortezomib and an immunomodulatory agent), in combination with panobinostat and dexamethasone†.
NOTE: Panobinostat is FDA approved in combination with bortezomib and dexamethasone for the treatment of multiple myeloma in patients who have received at least 2 prior therapies (including bortezomib and an immunomodulatory agent).
Intravenous dosage Adults

1.3 mg/m2 IV on days 1, 4, 8, and 11 in cycles 1 to 8 then bortezomib 1.3 mg/m2 on days 1 and 8 in cycles 9 to 16. Administer in combination with dexamethasone (20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12 in cycles 1 to 8 then 20 mg PO on days 1, 2, 8, and 9 in cycles 9 to 16) and panobinostat (20 mg PO on days 1, 3, 5, 8, 10, and 12). Continue every 21-day treatment cycles for up to 8 cycles; consider giving up to an additional 8 cycles (maximum of 16 treatment cycles) in patients who experience clinical benefit without unresolved severe or medically significant toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. Treatment with panobinostat, bortezomib, and dexamethasone (n = 387; median therapy duration of 5 months) was compared with placebo, bortezomib, and dexamethasone (n = 381; median therapy duration of 6.1 months) in patients with relapsed or relapsed and refractory multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, phase 3 trial (the PANORAMA1 trial). The median patient age was 63 years (range, 56 to 69 years), about 51% of patients had received 1 prior therapy, and approximately 57% of patients had previously received a stem-cell transplantation. Patients with primary refractory or bortezomib refractory disease were ineligible for this study. At a median follow-up time of 6.47 months, the median progression-free survival time (primary endpoint) was significantly improved in the panobinostat arm (11.99 months) compared with the placebo arm (8.08 months; hazard ratio [HR] = 0.63; 95% CI, 0.52 to 0.76; p less than 0.0001). The overall survival (OS) time was not significantly improved in the panobinostat arm (33.64 months vs. 30.39 months; HR = 0.87; 95% CI, 0.69 to 1.1); however, OS data are not mature. Crossover from the placebo arm to the panobinostat arm is not permitted.

For the treatment of multiple myeloma in patients who received at least 1 prior therapy, in combination with daratumumab and dexamethasone†.
NOTE: Daratumumab is FDA approved in combination with bortezomib and dexamethasone for this indication.
Subcutaneous dosage Adults

1.3 mg/m2 given as a subcutaneous injection on days 1, 4, 8, and 11 repeated every 3 weeks for 8 cycles in combination with daratumumab and dexamethasone was evaluated in a multinational, randomized, open-label, phase 3 trial (n = 498; CASTOR trial). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. The daratumumab dosage is 16 mg/kg (actual body weight) IV weekly on weeks 1 to 9 (9 doses), 16 mg/kg IV every 3 weeks on weeks 10 to 24 (5 doses), and then 16 mg/kg IV every 4 weeks starting on week 25 until disease progression or unacceptable toxicity; administer standard pre-and post-infusion medications with daratumumab infusions. The dexamethasone dosage is 20 mg PO/IV on days 1, 2, 4, 5, 8, 9, 11, and 12 repeated every 3 weeks for 8 cycles. Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years, with a body-mass index less than 18.5, or who had poorly controlled diabetes mellitus or a prior intolerance to glucocorticoid therapy.

For the treatment of newly diagnosed multiple myeloma, in combination with lenalidomide and dexamethasone†. Intravenous dosage Adults

1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 21 days for 8 cycles (SWOG S0777 trial); 1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 21 days for 3 cycles prior to stem-cell transplantation (SCT) followed by 2 cycles after SCT (IFM 2009 trial); and 1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 21 days for 8 cycles followed by 1.3 mg/m2 IV on days 1 and 8 in cycles 9 to 12 (ENDURANCE trial) in combination with lenalidomide and dexamethasone (VRd regimen) have been evaluated in 3 randomized, phase 3 trials. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 in cycles 1 to 8 and 1.3 mg/m2 subcutaneously on days 1 and 8 in cycles 9 to 12 in combination with lenalidomide and dexamethasone (VRd regimen) has been evaluated in a randomized, phase 3 trial (n = 1,087; ENDURANCE trial). Therapy cycles were repeated every 21 days. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with daratumumab, melphalan, and prednisone†.
NOTE: Daratumumab is FDA approved in combination with bortezomib, melphalan, and prednisone for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant.
Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 of cycle 1 followed by bortezomib 1.3 mg/m2 subcutaneously once weekly on weeks 1, 2, 4, and 5 of cycles 2 to 9; melphalan 9 mg/m2 orally daily on days 1, 2, 3, and 4; and prednisone 60 mg/m2 orally daily on days 1, 2, 3, and 4 (VMP regimen) repeated every 6 weeks for 9 cycles in combination with daratumumab was evaluated in a randomized, phase 3 trial. The manufacturer recommends the following daratumumab dosage in combination with VMP: 16 mg/kg (actual body weight) IV weekly on weeks 1 to 6, 16 mg/kg IV every 3 weeks on weeks 7 to 54, and then 16 mg/kg IV every 4 weeks starting on week 55 until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. In the ALCYONE trial (median follow-up of 40.1 months), the primary endpoint of PFS time was significantly higher with daratumumab plus VMP compared VMP alone (36.4 months vs. 19.3 months; hazard ratio (HR) = 0.42; 95% CI, 0.34 to 0.51; p less than 0.0001) in adult patients (n = 706; median age, 71 years; range, 40 to 93 years) with multiple myeloma who were ineligible for high-dose chemotherapy with stem-cell transplant (SCT) due to coexisting conditions or age of 65 years or older and who had not received prior systemic therapy or SCT. At the time of this analysis, the median overall survival time was significantly improved in patients in the daratumumab plus VMP arm compared with the VMP alone arm (median time not reached in either arm; HR = 0.6; 95% CI, 0.46 to 0.8; p = 0.0003).

For the treatment of relapsed or refractory multiple myeloma in patients who have received 1 to 3 prior therapies including lenalidomide, in combination with pomalidomide and dexamethasone†. Intravenous dosage Adults

1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 21 days on cycles 1 to 8 then 1.3 mg/m2 IV on days 1 and 8 starting on cycle 9 in combination with pomalidomide (4 mg orally daily on days 1 to 14) and dexamethasone was evaluated in a randomized, phase 3 trial (n = 559; the OPTIMISMM trial). Patients aged 75 years and younger received dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 on cycles 1 to 8 and then 20 mg orally on days 1, 2, 8, and 9 starting on cycle 9; patients older than 75 years received dexamethasone 10 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 on cycles 1 to 8 and then 10 mg orally on days 1, 2, 8, and 9 starting on cycle 9. Treatment cycles were repeated every 21 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 21 days on cycles 1 to 8 then 1.3 mg/m2 subcutaneously on days 1 and 8 starting on cycle 9 in combination with pomalidomide (4 mg orally daily on days 1 to 14) and dexamethasone was evaluated in a randomized, phase 3 trial (n = 559; the OPTIMISMM trial). Patients aged 75 years and younger received dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 on cycles 1 to 8 and then 20 mg orally on days 1, 2, 8, and 9 starting on cycle 9; patients older than 75 years received dexamethasone 10 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 on cycles 1 to 8 and then 10 mg orally on days 1, 2, 8, and 9 starting on cycle 9. Treatment cycles were repeated every 21 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of newly diagnosed multiple myeloma as induction and consolidation therapy in patients who are eligible for autologous stem-cell transplant, in combination with daratumumab, thalidomide, and dexamethasone†. Subcutaneous dosage Adults 65 years and younger

1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 28 days for up to 4 induction cycles and then 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 28 days for 2 consolidation cycles in combination with daratumumab, thalidomide, and dexamethasone was evaluated in a multicenter, randomized, phase 3 trial (n = 1,085; the CASSIOPEIA trial). In this trial, bortezomib was administered for up to four 28-day induction therapy cycles and two 28-day consolidation therapy cycles with daratumumab (16 mg/kg IV weekly in induction cycles 1 and 2 then 16 mg/kg IV every 2 weeks in induction cycles 3 and 4 and for both consolidation cycles), thalidomide (100 mg orally daily), and dexamethasone (40 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, and 23 in induction cycles 1 and 2; 40 mg PO/IV on days 1 and 2 and 20 mg PO/IV on days 8, 9, 15, and 16 in induction cycles 3 and 4; and 20 mg PO/IV on days 1, 2, 8, 9, 15, and 16 for both consolidation cycles). Consolidation therapy was begun after hematopoietic reconstitution but not earlier than 30 days after transplant.[64528] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.[28383]

For the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with daratumumab/hyaluronidase, melphalan, and prednisone†.
NOTE: Daratumumab; hyaluronidase is FDA approved in combination with bortezomib, melphalan, and prednisone for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant.
Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 for the first 6-week cycle (8 doses in cycle 1) followed by bortezomib 1.3 mg/m2 subcutaneously once weekly on weeks 1, 2, 4, and 5 for 8 more 6-week cycles (4 doses/cycle in cycles 2 to 9) in combination with melphalan 9 mg/m2 PO daily on days 1, 2, 3, and 4 repeated every 6 weeks on cycles 1 to 9; prednisone 60 mg/m2 PO daily on days 1, 2, 3, and 4 repeated every 6 weeks on cycles 1 to 9; and 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 6 (6 doses), every 3 weeks on weeks 7 to 54 (16 doses), and then every 4 weeks starting on week 55 until disease progression was evaluated in a single-arm cohort (n = 67) of a multicohort, open-label trial (the PLEIADES trial). The overall response rate was 88% in patients with newly diagnosed multiple myeloma who were ineligible for transplant who received daratumumab/hyaluronidase, bortezomib, melphalan, and prednisone. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of bortezomib and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of newly diagnosed multiple myeloma in patients who are eligible for autologous stem-cell transplant, in combination with daratumumab, lenalidomide, and dexamethasone†. Subcutaneous dosage Adults 70 years and younger

1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 21 days on cycles 1, 2, 3, and 4 followed by high-dose chemotherapy and an autologous stem-cell transplant and then 2 additional cycles of bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 21 days (cycles 5 and 6) plus lenalidomide 25 mg orally daily on days 1 to 14 and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16 repeated every 21 days for 6 cycles (VRd regimen) with daratumumab was evaluated in a randomized, phase 2 trial (the GRIFFIN trial; n = 207). Daratumumab treatment consisted of 16 mg/kg IV on days 1, 8, and 15 repeated every 21 days on cycles 1, 2, 3, and 4 and 16 mg/kg IV day 1 repeated every 21 days on cycles 5 and 6. Maintenance therapy was given for up to 2 years and consisted of daratumumab 16 mg/kg IV on day 1 repeated every 4 or 8 weeks and lenalidomide 10 mg orally daily on days 1 to 21 (increased to 15 mg after 3 cycles if tolerated) repeated every 28 days. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of multiple myeloma in patients who have received at least 1 prior therapy, in combination with selinexor and dexamethasone†.
NOTE: Selinexor is FDA approved in combination with bortezomib and dexamethasone for this indication.
Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously on day 1 once weekly for 4 weeks followed by 1 week off in combination with selinexor 100 mg orally on day 1 once weekly and dexamethasone 20 mg orally on days 1 and 2 of each week; repeat cycles until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. Treatment with a once-weekly regimen of selinexor plus bortezomib, and dexamethasone (SVd regimen) led to a significantly improved median progression-free survival time compared with bortezomib and dexamethasone (13.93 months vs. 9.46 months; hazard ratio (HR) = 0.7; 95% CI, 0.53 to 0.93) in a randomized, phase 3 trial (n = 402; the Boston trial). At a median follow-up of 17.3 months, the median overall survival (OS) time was not significantly improved in the SVd arm (HR = 0.84; 95% CI, 0.57 to 1.23); however, OS data was not mature at the time of this analysis. Patients (median age, 67 years) in this trial had received a median of 2 prior regimens (range, 1 to 2 regimens) and approximately 70% of patients had received prior bortezomib therapy; 35% of patients had previously received a stem-cell transplant.

For the treatment of mantle cell lymphoma (MCL).
NOTE: The FDA has designated bortezomib as an orphan drug for this indication.
For the treatment of relapsed MCL. Intravenous dosage Adults

1.3 mg/m2 IV twice weekly on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21). For extended therapy of more than 8 cycles, administer bortezomib on the standard 3-week cycle or once weekly (on days 1, 8, 15, and 22) followed by a 13-day rest period (on days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. In a phase 2 clinical trial, 155 patients with MCL were treated as above for a median of 4 cycles, although patients that responded were treated for a median of 8 cycles; 91% (n = 141) of patients were evaluated for response with an overall response rate of 33%; 8% of patients had a complete response (CR) or an unconfirmed complete response (CRu), and 26% achieved a partial response (PR). Median duration of response was 9.2 months, although in patients with a CR/CRu the median duration of response was 13.5 months. Median time to progression for all patients was 6.2 months. After a median follow-up of 13.4 months, 66% of patients were still alive. One-year survival rates for all patients, responding patients, and CR/CRu patients were 69.3%, 94.3%, and 100%, respectively. Other studies have also demonstrated benefit in patients with MCL using the approved dosage.

Subcutaneous dosage

NOTE: The subcutaneous route may be the preferred route of administration in patients with pre-existing peripheral neuropathy or who have a high risk of developing peripheral neuropathy.

Adults

1.3 mg/m2 as a subcutaneous injection twice weekly on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21). For extended therapy of more than 8 cycles, administer bortezomib on the standard 3-week cycle or once weekly (on days 1, 8, 15, and 22) followed by a 13-day rest period (on days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities. In a phase 2 clinical trial, 155 patients with MCL were treated as above for a median of 4 cycles, although patients that responded were treated for a median of 8 cycles; 91% (n = 141) of patients were evaluated for response with an overall response rate of 33%; 8% of patients had a complete response (CR) or an unconfirmed complete response (CRu), and 26% achieved a partial response (PR). Median duration of response was 9.2 months, although in patients with a CR/CRu the median duration of response was 13.5 months. Median time to progression for all patients was 6.2 months. After a median follow-up of 13.4 months, 66% of patients were still alive. One-year survival rates for all patients, responding patients, and CR/CRu patients were 69.3%, 94.3%, and 100%, respectively. Other studies have also demonstrated benefit in patients with MCL using the approved dosage.

For the treatment of previously untreated MCL, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone.
NOTE: The subcutaneous route may be the preferred route of administration in patients with pre-existing peripheral neuropathy or who have a high risk of developing peripheral neuropathy.
Intravenous or Subcutaneous dosage Adults

1.3 mg/m2 IV or as a subcutaneous injection twice weekly on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21) for six 3-week cycles in combination with rituximab (375 mg/m2 IV on day 1), cyclophosphamide (750 mg/m2 IV on day 1), doxorubicin (50 mg/m2 IV on day 1), and prednisone (100 mg/m2 PO daily on days 1, 2, 3, 4, and 5). Administer bortezomib prior to rituximab on day 1 of each cycle. Patients who have a response at cycle 6 may continue therapy for 2 additional cycles (maximum of 8 cycles). At least 72 hours should elapse between consecutive doses of bortezomib. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.[28383] The median progression-free survival (PFS) time (primary endpoint) was significantly improved with bortezomib (IV), rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) compared with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle cell lymphoma who were transplant ineligible (median age, 66 years; range, 26 to 88 years) in a multicenter, randomized, open-label, phase 3 study (n = 487; LYM-3002 study). A median of 6 cycles was administered in both treatment arms (range, 1 to 8 cycles). At a median follow-up of 40 months, the median PFS time was 24.7 months in the VcR-CAP arm and 14.4 months in the R-CHOP arm (hazard ratio (HR) = 0.63; 95% CI, 0.5 to 0.79; p less than 0.001), as assessed by an independent radiology review committee.[59223] At a median follow-up of 82 months, the median overall survival (OS) time was significantly improved in the VcR-CAP arm (90.7 months vs 55.7 months; HR = 0.66; 95% CI, 0.51 to 0.85). The 6-year OS rates were 56.6% and 42% in the VcR-CAP and R-CHOP arms, respectively.[64080]

For the treatment of relapsed or refractory indolent B-cell non-Hodgkin's lymphoma (NHL)†.
NOTE: The FDA has designated bortezomib as an orphan drug for this indication.
Intravenous dosage Adults

1.3 mg/m2 IV twice weekly (on days 1, 4, 8, and 11) and repeated every 21 days or 1.6 mg/m2 IV once weekly (on days 1, 8, 15, and 22) and repeated every 35 days with or without rituximab (375 mg/m2 once weekly for 4 weeks) has been studied. In a multicenter, phase 2 study of 53 patients with indolent B-cell non-Hodgkin lymphoma who had received at least 1 prior treatment regimen that contained rituximab, twice-weekly bortezomib for up to 8 cycles resulted in an overall response rate (ORR) of 13.3% (complete remission [CR], 7.5%), a median progression-free survival (PFS) time of 5.1 months, and a median overall survival time of 27.7 months. All patients received allopurinol 300 mg/day for the first 30 days of treatment. In another multicenter, phase 2 trial in 81 patients with relapsed or refractory follicular or marginal-zone B-cell NHL, combination therapy with rituximab plus either twice weekly bortezomib for 5 cycles or once weekly bortezomib for 3 cycles led to ORR of 44% (CR, 12%) and 43% (CR, 10%) and median PFS times of 5 months and 10 months in the twice weekly and once weekly arms, respectively. Grade 3 or 4 thrombocytopenia, neutropenia, vomiting, and peripheral neuropathy occurred more often in the twice weekly arm. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of Waldenstrom macroglobulinemia†. For the treatment of newly diagnosed Waldenstrom macroglobulinemia, in combination with dexamethasone and rituximab†. Intravenous dosage Adults

1.3 mg/m2 IV on days 1, 4, 8, and 11 for the first 21-day cycle (cycle 1) then bortezomib 1.6 mg/m2 IV on days 1, 8, 15, and 22 repeated every 35 days for 4 additional cycles (cycles 2, 3, 4, and 5) in combination with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 in cycles 2 and 5 (for 8 total doses) and dexamethasone 40 mg IV on days 1, 8, 15, and 22 in cycles 2 and 5 was evaluated in a nonrandomized phase II trial. All patients received premedication with acetaminophen 1,000 mg PO and diphenhydramine 50 mg IV prior to rituximab and herpes zoster prophylaxis with valacyclovir or acyclovir. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of amyloidosis†. For the treatment of newly diagnosed systemic amyloid light-chain amyloidosis in patients who are ineligible for stem-cell transplantation, in combination with melphalan and dexamethasone†. Intraveneous dosage Adults

1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 28 days on cycles 1 and 2 and then bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 repeated every 35 days up to a maximum of 8 cycles in combination with melphalan and dexamethasone (BMdex regimen) was evaluated in a multicenter, randomized, open-label, phase 3 trial (n = 109). Patients were evaluated for response after 3 and 6 cycles of therapy; patients with a partial response (PR) or better after cycle 3 received an additional 3 cycles of therapy. Patients with a complete response (CR) or a PR and organ response stopped treatment after cycle 6. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 28 days on cycles 1 and 2 and then bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 repeated every 35 days up to a maximum of 8 cycles in combination with melphalan and dexamethasone (BMdex regimen) was evaluated in a multicenter, randomized, open-label, phase 3 trial (n = 109). Patients were evaluated for response after 3 and 6 cycles of therapy; patients with a partial response (PR) or better after cycle 3 received an additional 3 cycles of therapy. Patients with a complete response (CR) or a PR and organ response stopped treatment after cycle 6. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

For the treatment of newly diagnosed light-chain amyloidosis, in combination with daratumumab; hyaluronidase, cyclophosphamide, and dexamethasone†.
NOTE: Daratumumab; hyaluronidase is FDA approved in combination with bortezomib, cyclophosphamide, and dexamethasone for the treatment of newly diagnosed light-chain amyloidosis.
Subcutaneous dosage Adults

1.3 mg/m2 subcutaneously in combination with cyclophosphamide 300 mg/m2 (Max dose of 500 mg) IV/PO and dexamethasone 40 mg IV/PO each given weekly on days 1, 8, 15, and 22 repeated every 28 days for a maximum of 6 cycles (VCd) plus up to 2 years of subcutaneous daratumumab; hyaluronidase (D-VCd) was evaluated in transplant eligible, newly diagnosed light-chain amyloidosis patients in a randomized, phase 3 trial (n = 388; the ANDROMEDA trial). The dose of dexamethasone was reduced to 20 mg in patients older than 70 years or who had a body mass index less than 18.5, hypervolemia, poorly controlled diabetes mellitus, or prior intolerance to steroid therapy. Daratumumab; hyaluronidase was administered as follows: 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), 1,800 mg daratumumab and 30,000 units hyaluronidase every 2 weeks on weeks 9 to 24 (8 doses), and then 1,800 mg daratumumab and 30,000 units hyaluronidase every 4 weeks starting on week 25 until disease progression or for a maximum of 2 years. At a median follow-up time of 11.4 (range, 0.03 to 21.3) months, the hematologic complete response rate (hemCR) was significantly improved (53.3% vs. 18.1%; relative risk ratio = 2.9; 95% CI, 2.1 to 4.1; p less than 0.001) in patients who received D-VCd compared with VCd in the ANDROMEDA trial. The median time to hemCR was 60 and 85 days in the D-VCd and VCd arms, respectively. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption or discontinuation of therapy and/or a dose reduction may be necessary in patients who develop toxicities.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Mild hepatic impairment (bilirubin level less than the ULN and any AST level more than the ULN OR bilirubin level more than 1 to 1.5 times the ULN and any AST level): No bortezomib dosage adjustment necessary.
Moderate (bilirubin level more than 1.5 to 3 times the ULN and any AST level) or severe (bilirubin level more than 3 times the ULN and any AST level) hepatic impairment: Initiate therapy at a reduced bortezomib dose of 0.7 mg/m2 on the first cycle; in subsequent cycles, escalate the dose to 1 mg/m2 or reduce the dose further to 0.5 mg/m2 based on patient tolerability.

Renal Impairment

No bortezomib dosage adjustment necessary for renal impairment.
 
Intermittent hemodialysis
Administer bortezomib after dialysis.

Drug Interactions

Abacavir; Dolutegravir; Lamivudine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Abacavir; Lamivudine, 3TC: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like zidovudine; the risk of peripheral neuropathy may be additive.
Adagrasib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of adagrasib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased bortezomib exposure by 35%.
Albuterol; Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Alogliptin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Alpha-blockers: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Alpha-glucosidase Inhibitors: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Amiloride: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Amiodarone: (Minor) Amiodarone inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity.
Amobarbital: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive effects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects. Some protocols recommend decreasing the dosage of the standard immunosuppressive agents during treatment with antithymocyte globulin. Carefully observe patients for new adverse effects if the dose of immunosuppressants is reduced, as adverse effects of antithymocyte globulin may have been masked.
Apalutamide: (Major) Coadministration of apalutamide with bortezomib is not recommended due to decreases in bortezomib plasma concentrations. Bortezomib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer is expected to decrease the exposure of bortezomib by at least 45%.
Aprepitant, Fosaprepitant: (Moderate) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and may be used in combination with bortezomib. However, use caution and monitor for an increase in non-emetogenic bortezomib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Bortezomib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and could theoretically increase plasma concentrations of bortezomib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as bortezomib, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Carisoprodol; Codeine: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as bortezomib, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Atazanavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such atazanavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, atazanavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy.
Atazanavir; Cobicistat: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such atazanavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, atazanavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy. (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Barbiturates: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of bortezomib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and bortezomib is a CYP2C19 inhibitor.
Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like metronidazole; the risk of peripheral neuropathy may be additive.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like metronidazole; the risk of peripheral neuropathy may be additive.
Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Butabarbital: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Butalbital; Acetaminophen: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Butalbital; Acetaminophen; Caffeine: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Calcium-channel blockers: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Canagliflozin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Canagliflozin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as bortezomib, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Central-acting adrenergic agents: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Ceritinib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ceritinib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Chloramphenicol: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like chloramphenicol; the risk of peripheral neuropathy may be additive.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Cimetidine: (Minor) Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with cimetidine is not known.
Ciprofloxacin: (Minor) Plasma concentrations of bortezomib may be elevated when administered concurrently with ciprofloxacin. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
Clarithromycin: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cobicistat: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Colchicine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like colchicine; the risk of peripheral neuropathy may be additive.
Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Cyclosporine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like cyclosporine; the risk of peripheral neuropathy may be additive.
Dapagliflozin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Dapagliflozin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Dapagliflozin; Saxagliptin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Dapsone: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like dapsone; the risk of peripheral neuropathy may be additive.
Darunavir: (Moderate) The plasma concentrations of bortezomib may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
Darunavir; Cobicistat: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%. (Moderate) The plasma concentrations of bortezomib may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%. (Moderate) The plasma concentrations of bortezomib may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Delavirdine: (Minor) Agents that inhibit cytochrome P450 3A4, such as delavirdine, may increase the exposure to bortezomib and increase the risk for toxicity.
Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Diazoxide: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Didanosine, ddI: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like didanosine; the risk of peripheral neuropathy may be additive.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Disulfiram: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like disulfiram; the risk of peripheral neuropathy may be additive.
Docetaxel: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like docetaxel; the risk of peripheral neuropathy may be additive.
Dolutegravir; Lamivudine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Doxazosin: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Efavirenz: (Moderate) Agents that induce CYP3A4, such as efavirenz, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of a potential interaction resulting from the concurrent administration of bortezomib with efavirenz is not known.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Agents that induce CYP3A4, such as efavirenz, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of a potential interaction resulting from the concurrent administration of bortezomib with efavirenz is not known.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Agents that induce CYP3A4, such as efavirenz, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of a potential interaction resulting from the concurrent administration of bortezomib with efavirenz is not known. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Empagliflozin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Empagliflozin; Linagliptin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Empagliflozin; Linagliptin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Empagliflozin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Enzalutamide: (Major) Coadministration of enzalutamide with bortezomib is not recommended due to decreases in bortezomib plasma concentrations. Bortezomib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer is expected to decrease the exposure of bortezomib by at least 45%.
Eplerenone: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Epoprostenol: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Ertugliflozin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Ertugliflozin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Ertugliflozin; Sitagliptin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Erythromycin: (Minor) Erythromycin can inhibit the hepatic metabolism of other drugs, such as borezomib, increasing their serum concentrations and potentially causing toxicity. If therapy with erythromycin is necessary, a reduction in the dose of bortezomib may be required. Such patients should be monitored carefully and lower doses should be used.
Ethotoin: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including bortezomib, leading to reduced efficacy of the concomitant medication.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as bortezomib, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of bortezomib during coadministration with fenofibric acid.
Fenoldopam: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Fluconazole: (Minor) Fluconazole inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluconazole is not known.
Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Fluoxetine: (Minor) Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluoxetine is not known.
Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Fosamprenavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such fosamprenavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity.
Fosphenytoin: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including bortezomib, leading to reduced efficacy of the concomitant medication.
Glipizide; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Glyburide; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Grapefruit juice: (Minor) The manufacturer warns that patients who are receiving bortezomib concurrently with CYP3A4 inhibitors, such as grapefruit juice, should be closely monitored for potential toxicity.
Green Tea: (Major) Green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, have been shown to effectively inhibit bortezomib-induced tumor cell death in multiple myeloma and glioblastoma cell lines in vitro and in vivo. EGCG directly reacts with boronic-acid based proteasome inhibitors, like bortezomib, and blocks the proteasome inhibitory function. As a result, when bortezomib and green tea products are coadministered, bortezomib cannot trigger endoplasmic reticulum stress or capsase-7 activation and therefore, cannot induce tumor cell death. This interaction is likely to occur in humans at concentrations of 2-5 mcM EGCG, which are achievable with the use of green tea supplements. The authors of this study suggest that it may be prudent to avoid green tea when patients with multiple myeloma or glioblastoma are receiving bortezomib.
HMG-CoA reductase inhibitors: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including bortezomib, leading to reduced efficacy of the concomitant medication.
Hydralazine: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension (including orthostatic hypotension) was reported in roughly 12 percent of patients; most events were mild to moderate in severity, with more dramatic hypotension reported in 4 percent of drug recipients. Additionally, bortezomib and hydralazine can both cause peripheral neuropathy; coadminister these drugs cautiously, as the risk of peripheral neuropathy may be additive.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension (including orthostatic hypotension) was reported in roughly 12 percent of patients; most events were mild to moderate in severity, with more dramatic hypotension reported in 4 percent of drug recipients. Additionally, bortezomib and hydralazine can both cause peripheral neuropathy; coadminister these drugs cautiously, as the risk of peripheral neuropathy may be additive.
Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Idelalisib: (Major) Coadministration of idelalisib with bortezomib may increase bortezomib exposure. If these drugs are used together, consider a bortezomib dose reduction and monitor patients for signs and symptoms of bortezomib-related adverse reactions (e.g., peripheral neuropathy and hematologic toxicity). Idelalisib is a strong CYP3A4 inhibitor and bortezomib is a CYP3A substrate. The mean bortezomib AUC value increased by 35% when bortezomib was administered with another strong CYP3A inhibitor in a drug interaction study (n = 12).
Iloprost: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Imatinib: (Minor) Agents that inhibit cytochrome P450 3A4, such as imatinib, may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with CYP3A4 inhibitors is not known.
Incretin Mimetics: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Indinavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such indinavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity.
Insulins: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Iodoquinol: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like iodoquinol; the risk of peripheral neuropathy may be additive.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with bortezomib may result in increased serum concentrations of bortezomib. Bortezomib is metabolized by the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of bortezomib.
Isoniazid, INH; Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of bortezomib.
Itraconazole: (Moderate) Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with itraconazole. Bortezomib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadminsitration or another strong CYP3A4 inhibitor increased the exposure of bortezomib by 35%.
Ketoconazole: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ketoconazole is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Lamivudine, 3TC: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like zidovudine; the risk of peripheral neuropathy may be additive.
Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
Letermovir: (Moderate) Administering letermovir with bortezomib may increase bortezomib concentration and risk for adverse events. Consider a bortezomib dose reduction and monitor for signs of bortezomib toxicity if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Bortezomib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased exposure of bortezomib by 35%.
Levoketoconazole: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ketoconazole is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Linagliptin; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Lonafarnib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of lonafarnib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Lopinavir; Ritonavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such ritonavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, ritonavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy.
Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of bortezomib, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of bortezomib, such as peripheral neuropathy, hematologic toxicities, and GI events. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bortezomib by decreasing its systemic exposure; avoid concurrent use. Bortezomib is primarily metabolized by CYP3A4 and is also a substrate of CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2C19. Drug interaction studies suggest coadministration of bortezomib and rifampin, another strong CYP3A inducer, reduces bortezomib exposure by at least 45%.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting bortezomib therapy. Avoid initiation of bortezomib in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable bortezomib therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and bortezomib is a weak CYP2C19 inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Mecamylamine: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Meglitinides: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Metformin; Repaglinide: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Metformin; Rosiglitazone: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Metformin; Saxagliptin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Metformin; Sitagliptin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Methohexital: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Metronidazole: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like metronidazole; the risk of peripheral neuropathy may be additive.
Mifepristone: (Moderate) Bortezomib is partially metabolized by CYP3A4; mifepristone is a strong CYP3A4 inhibitor. Consider a bortezomib dose reduction if bortezomib is administered with a strong CYP3A4 inhibitor like mifepristone. The effects of mifepristone on drug metabolism may be prolonged due to its long half-life.
Minoxidil: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Mitotane: (Major) Avoid the concomitant use of mitotane with bortezomib; if coadministration cannot be avoided, monitor for decreased efficacy of bortezomib. Mitotane is a strong CYP3A4 inducer and bortezomib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of bortezomib.
Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Nefazodone: (Minor) Bortezomib is a significant substrate for CYP3A4. Nefazodone inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity.
Nelfinavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such nelfinavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as bortezomib. The plasma concentrations of bortezomib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nirmatrelvir; Ritonavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such ritonavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, ritonavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy.
Nitrofurantoin: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like nitrofurantoin; the risk of peripheral neuropathy may be additive.
Nitroprusside: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Olanzapine; Fluoxetine: (Minor) Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluoxetine is not known.
Olopatadine; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Agents that induce CYP3A4, such as rifabutin, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with CYP3A4 inducers is not known.
Oritavancin: (Moderate) Bortezomib is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of bortezomib may be reduced if these drugs are administered concurrently.
Paclitaxel: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like paclitaxel; the risk of peripheral neuropathy may be additive.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and bortezomib, a CYP3A4 substrate, may cause an increase in systemic concentrations of bortezomib. Use caution when administering these drugs concomitantly.
Pentobarbital: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Phenicol Derivatives: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like chloramphenicol; the risk of peripheral neuropathy may be additive.
Phenobarbital: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Phenoxybenzamine: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Phentolamine: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Phenytoin: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including bortezomib, leading to reduced efficacy of the concomitant medication.
Pioglitazone; Metformin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Posaconazole: (Moderate) Posaconazole and bortezomib should be coadministered with caution due to an increased potential for bortezomib-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of bortezomib. These drugs used in combination may result in elevated bortezomib plasma concentrations, causing an increased risk for bortezomib-related adverse events.
Potassium-sparing diuretics: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Pramlintide: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Prazosin: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Primidone: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Probenecid; Colchicine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like colchicine; the risk of peripheral neuropathy may be additive.
Ribociclib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ribociclib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Ribociclib; Letrozole: (Moderat

e) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ribociclib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Rifabutin: (Minor) Agents that induce CYP3A4, such as rifabutin, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with CYP3A4 inducers is not known.
Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of bortezomib.
Rifapentine: (Major) Coadministration of rifapentine with bortezomib is not recommended as concurrent use may decrease bortezomib exposure which may lead to decreased efficacy. Bortezomib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer is expected to decrease the exposure of bortezomib by at least 45%.
Ritonavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such ritonavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, ritonavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as bortezomib, may occur during concurrent use with rufinamide.
Saquinavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such saquinavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
SGLT2 Inhibitors: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Sotagliflozin: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Spironolactone: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
St. John's Wort, Hypericum perforatum: (Minor) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including bortezomib.
Stavudine, d4T: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like stavudine; the risk of peripheral neuropathy may be additive.
Sulfasalazine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like sulfasalazine; the risk of peripheral neuropathy may be additive.
Sulfonylureas: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Tacrolimus: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like tacrolimus; the risk of peripheral neuropathy may be additive.
Terazosin: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Thalidomide: (Moderate) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like thalidomide; the risk of peripheral neuropathy may be additive.
Thiazide diuretics: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Thiazolidinediones: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Tipranavir: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for cytochrome P450 3A4. Agents that inhibit CYP3A4, such as tipranavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with CYP3A4 inhibitors should be closely monitored for potential toxicity.
Treprostinil: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
Triamterene: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Tucatinib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of tucatinib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as bortezomib, could be expected with concurrent use. Use caution, and monitor therapeutic effects of bortezomib when coadministered with vemurafenib.
Vincristine Liposomal: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like vincristine; the risk of peripheral neuropathy may be additive.
Vincristine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like vincristine; the risk of peripheral neuropathy may be additive.
Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
Voriconazole: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of voriconazole is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Zidovudine, ZDV: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like zidovudine; the risk of peripheral neuropathy may be additive.

How Supplied

Bortezomib Intravenous Inj Sol: 1mL, 2.5mg
Bortezomib/Velcade Intravenous Inj Pwd F/Sol: 1mg, 2.5mg, 3.5mg
Bortezomib/Velcade Subcutaneous Inj Pwd F/Sol: 1mg, 2.5mg, 3.5mg

Maximum Dosage
Adults

1.3 mg/m2 per dose IV or subcutaneously; 1.6 mg/m2 per dose IV has also been studied.

Geriatric

1.3 mg/m2 per dose IV or subcutaneously; 1.6 mg/m2 per dose IV has also been studied.

Adolescents

Safety and efficacy not established.

Children

Safety and efficacy not established.

Infants

Safety and efficacy not established.

Mechanism Of Action

Bortezomib is a reversible inhibitor of the 26S proteasome in mammalian cells, which is part of the ubiquitin-proteasome pathway. A proteasome is a large multiprotein particle present in the cytosol and cell nucleus that is responsible for the regulation of protein expression and the degradation of damaged or obsolete proteins within the cell; its activity is critical to activation or suppression of cellular functions. This system regulates the expression of proteins mediating cell cycle progression (p21cip, p27kip, cyclins), oncogenes (p53), and apoptosis (Bcl, cIAP, XIAP, Bax); inhibition of the breakdown of these proteins has been associated with sensitization of the cell to apoptosis. Malignant cells are much more sensitive to the effects of proteasome inhibition than normal cells. In normal cells, checkpoint mechanisms arrest cell division when irregularities in cell cycle regulators are noted; cell division is allowed to continue only after proteasome activity has been restored. In tumor cells however, genetic changes that accompany malignant transformation disable the checkpoint mechanisms. Thus, proteasome inhibition may reverse some of the changes that allow proliferation and suppress apoptosis in the malignant cell.
 
Bortezomib has been shown to inhibit the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) through stabilization of the inhibitor protein I kappa B kinase (IKK). Myeloma cells depend on the NF-kappa B pathway for transcription of growth factors such as interleukin-6, vascular endothelial growth factor (VEGF) for angiogenesis, VCAM-1, a cell adhesion molecule important in the adherence of the plasma cells to the stromal tissue in bone marrow, and other proteins (e.g., Bcl-2) that enhance myeloma cell survival and resistance to chemotherapy. At low concentrations (nanomolar), bortezomib is effective in inhibiting the transcription of these genes. However, inhibition of NF-kappa B may not be the only role of bortezomib in multiple myeloma. Bortezomib appears to be synergistic with dexamethasone in cell culture due to the inhibition of insulin-like growth factor-1 (IGF-1), which is thought to responsible for resistance to dexamethasone in multiple myeloma. Additional in vitro studies have shown that bortezomib decreases the levels of several anti-apoptotic proteins and induces a dual pathway of apoptosis in myeloma cells.

Pharmacokinetics

Bortezomib is administered as an intravenous bolus injection or a subcutaneous injection. The mean distribution volume of bortezomib ranged from about 498 to 1,884 L/m2, the mean elimination half-life ranged from 40 to 193 hours, and the mean total body clearance ranged from 15 to 112 L/hour in multiple myeloma patients who received single or repeat IV doses of bortezomib 1 mg/m2 (n = 12) or 1.3 mg/m2 (n = 12). Bortezomib appears to distribute widely into peripheral tissues; on average, it is 83% bound to human plasma proteins over a concentration range of 100 to 1,000 nanograms/mL. In vitro, bortezomib primarily undergoes oxidative metabolism via CYP450 isoenzymes. Deboronation occurs to form 2 metabolites that then undergo hydroxylation to form several metabolites; the 2 initial metabolites appear to be inactive as 26S proteasome inhibitors. The elimination pathways of bortezomib have not been determined in humans. The maximal inhibition of 20S proteasome activity in whole blood was 73% to 83% with a bortezomib 1.3 mg/m2 dose given twice weekly and was noted 5 minutes after administration.
 
Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C19
Bortezomib is a substrate of CYP3A4, CYP2C19 and CYP1A2; metabolism via CYP2D6 and CYP2C9 isoenzymes is minor. In vitro, bortezomib is a weak inhibitor of CYP1A2, CYP2C9, CYP2D6, and CYP3A4; it is not a CYP3A4 or CYP1A2 inducer. Bortezomib may inhibit CYP2C19 and increase exposure to drugs that are substrates for this enzyme. Increased or decreased bortezomib exposure may occur with the concomitant use of CYP3A4 inhibitors or CYP3A4 inducers, respectively. Avoid the use of CYP3A4 inducers during bortezomib therapy; closely monitor patients for toxicity and consider a bortezomib dose reduction if bortezomib is administered with a strong CYP3A4 inhibitor. The co-administration of bortezomib with a weak CYP3A4 inducer, dexamethasone, did not affect bortezomib exposure in a drug interaction study (n = 7). Additionally, the co-administration of bortezomib with a strong CYP2C19 inhibitor, omeprazole, did not affect bortezomib exposure in a drug interaction study (n = 17).

Intravenous Route

The Cmax values ranged from 89 to 120 nanograms/mL in multiple myeloma patients who received repeat IV doses of twice weekly bortezomib 1.3 mg/m2 (n = 12).

Subcutaneous Route

The total systemic exposure values were equivalent following repeat bortezomib doses of 1.3 mg/m2 given intravenously or subcutaneously in multiple myeloma patients; the AUC geometric mean ratio was 0.99 (90% CI, 0.8 to 1.23). The Cmax value was lower following subcutaneous administration compared with intravenous administration (20.4 ng/mL vs. 223 ng/mL).

Pregnancy And Lactation
Pregnancy

Bortezomib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies; there are no data on the use of bortezomib in pregnant women. Females of reproductive potential should avoid pregnancy during treatment with bortezomib. Advise pregnant women of the potential risk to the fetus. Administration to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a reduced number of live fetuses.

Counsel patients about the reproductive risk and contraception requirements during bortezomib treatment. Pregnancy testing should be performed prior to starting bortezomib in female patients of reproductive potential. Female patients of reproductive potential should use effective contraception during and for 7 months after the last dose of bortezomib. Due to the risk of male-mediated teratogenicity, male patients with a female partner of reproductive potential should use effective contraception during bortezomib therapy and for 4 months after the last dose. Women who become pregnant while receiving bortezomib should be apprised of the potential hazard to the fetus. There is a risk of male or female infertility with bortezomib therapy based on its mechanism of action and data from animal studies.[28383]