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  • CLASSES

    Other Antineoplastic Agents

    DEA CLASS

    Rx

    DESCRIPTION

    A proteasome inhibitor antineoplastic agent
    FDA-approved 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

    COMMON BRAND NAMES

    Velcade

    HOW SUPPLIED

    Bortezomib/Velcade Intravenous Inj Pwd F/Sol: 3.5mg
    Velcade Subcutaneous Inj Pwd F/Sol: 3.5mg

    DOSAGE & 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 over 3 to 5 seconds 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 < 0.001) in patients with previously untreated multiple myeloma who were transplant ineligible in a multinational, randomized, phase III 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 < 0.001); 5-year OS rates were 46% and 34.4%, respectively.

    Subcutaneous dosage (Velcade only)
    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 < 0.001) in patients with previously untreated multiple myeloma who were transplant ineligible in a multinational, randomized, phase III 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 < 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 over 3 to 5 seconds 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 < 0.001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, phase III 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 < 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 II 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 (Velcade only)
    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 III 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 < 0.001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, phase III 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 < 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 II 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 over 3 to 5 seconds 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 < 0.000004) in patients with relapsed or refractory multiple myeloma who had received at least 1 prior therapy in a multinational, randomized, phase III 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 III 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 III 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 III 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 (Velcade only).
    Intravenous or Subcutaneous dosage
    Adults

    Begin treatment at the last tolerated bortezomib dose, IV or subcutaneous, 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 II 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 push on 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 III 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 over 3 to 5 seconds 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 III 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 < 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 (Velcade only)
    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 III 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 in combination with lenalidomide (25 mg PO daily on days 1 to 14) and dexamethasone (20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12) repeated every 21 days (VRd regimen) for 8 cycles was evaluated in a randomized, phase III trial (n = 471; SWOG S0777 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. Following induction therapy, patients received maintenance therapy with lenalidomide 25 mg/day on days 1 to 21 and dexamethasone 40 mg orally on days 1, 8, 15, and 22 repeated every 28 days; the median duration of maintenance therapy was 385 days. All patients received herpes simplex virus prophylaxis and thromboembolic prophylaxis with aspirin 325 mg/day.

    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 in patients who have received at least 1 prior therapy.
    Intravenous dosage
    Adults

    1.3 mg/m2 IV over 3 to 5 seconds 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 II 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 (Velcade only)

    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 II 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 (Velcade only).
    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 over 3 to 5 seconds 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. 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 III 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 < 0.001), as assessed by an independent radiology review committee. At the time of this analysis, the median overall survival (OS) time was not significantly different between the treatment arms (median time not reached vs. 56.3 months; HR = 0.8; 95% CI, 0.59 to 1.1).The 4-year OS rates were 64% and 54% in the VcR-CAP and R-CHOP arms, respectively.

    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 II 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 II 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1.3 mg/m2 IV or subcutaneously.

    Geriatric

    1.3 mg/m2 IV or subcutaneously.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (bilirubin level less than the upper limit of normal (ULN and any AST level greater than the ULN or bilirubin level greater than 1 to 1.5-times the ULN and any AST level): No bortezomib dosage adjustment necessary.
    Moderate (bilirubin level greater than 1.5 to 3-times the ULN and any AST level) or severe (bilirubin level greater 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 dosage adjustments are needed.
     
    Intermittent hemodialysis
    Administer bortezomib after the dialysis procedure, as dialysis may reduce bortezomib concentrations.

    ADMINISTRATION

    CAUTION: Observe and exercise usual cautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Add 3.5 mL of 0.9% sodium chloride for injection to the 3.5-mg lyophilized vial for a final concentration of 1 mg/mL.
    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 following reconstitution: Store at 25 degrees C (77 degrees F) for up to 8 hours.
    Intravenous injection:
    Inject as an IV bolus over 3 to 5 seconds.

    Subcutaneous Administration

    Reconstitution:
    Add 1.4 mL or 3.5 mL of 0.9% sodium chloride for injection to the 3.5-mg lyophilized vial for a final concentration of 2.5 mg/mL or 1 mg/mL, respectively.
    Use the less concentrated solution of 1 mg/mL if a local injection-site reaction occurs with the 2.5 mg/mL solution.
    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 or 2.5 mg/mL); discard any unused drug remaining in the vial.
    Place a sticker that indicates subcutaneous administration on the syringe.
    Storage following reconstitution: Store at 25 degrees C (77 degrees F) for up to 8 hours.
    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; new sites should be at least 1 inch from an old site.

    STORAGE

    Velcade:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Mannitol hypersensitivity

    Bortezomib is contraindicated in patients with bortezomib hypersensitivity, boron hypersensitivity, or mannitol hypersensitivity. Bortezomib is a modified dipeptidyl boronic acid, and mannitol is an inactive ingredient in the product.

    Intrathecal administration


    Intrathecal administration of bortezomib is contraindicated. Fatal events have occurred with intrathecal administration of this drug.

    Peripheral neuropathy

    Severe sensory and motor peripheral neuropathy has been reported with bortezomib use. In patients with preexisting severe neuropathy, perform a risk-benefit analysis prior to starting bortezomib therapy; consider subcutaneous administration in these patients or in high-risk patients. Monitor patients for symptoms of neuropathy such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Bortezomib therapy may need to be held, dose reduced, and/or discontinued in patients who develop new or worsening peripheral neuropathy.

    Dehydration, hypotension, orthostatic hypotension, syncope

    Hypotension, including postural and orthostatic hypotension, has been reported with bortezomib use. Patients with dehydration, a history of syncope, or who are receiving medications associated with hypotension may be at increased risk for developing hypotension; use bortezomib with caution in these patients. Management of hypotension may include hydration, mineralocorticoid or sympathomimetic therapy, and/or adjustment of antihypertensive agents. In patients who develop gastrointestinal (GI) adverse events, give fluid and electrolyte replacement to prevent dehydration; bortezomib therapy may need to be held for severe GI toxicity.

    Cardiac disease, heart failure, pulmonary disease

    Cardiotoxicity has been reported in patients who received bortezomib in clinical trials, including acute onset congestive heart failure, decreased left ventricular ejection fraction, and rare cases of QT prolongation. Additionally, serious and sometimes fatal pulmonary disease (e.g., pulmonary hypertension, acute respiratory distress syndrome, pneumonitis, interstitial pneumonia, lung infiltration) has occurred with bortezomib use. Closely monitor patients with pre-existing, or risk factors for, cardiac disease; also monitor all patients for symptoms of new or worsening pulmonary symptoms. Hold bortezomib therapy pending a diagnostic evaluation in patients who develop new or worsening cardiopulmonary symptoms.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported with bortezomib use. Patients with a high tumor burden prior to treatment are at risk for TLS and should be carefully monitored during bortezomib therapy.

    Anemia, bleeding, GI bleeding, herpes infection, intracranial bleeding, neutropenia, thrombocytopenia

    Hematologic toxicity (e.g., thrombocytopenia, neutropenia, and anemia) has been reported with bortezomib use. Additionally, serious bleeding (i.e., GI bleeding, intracranial bleeding) has occurred in bortezomib-treated patients with thrombocytopenia; transfusions may be required in some cases. Monitor complete blood counts frequently during therapy and obtain a platelet count prior to each bortezomib dose. Therapy may need to be held and dose reduced in patients who develop severe hematologic toxicity. Consider using prophylactic antiviral therapy to prevent herpes infection and herpes zoster virus reactivation.

    Hepatic disease, hepatitis

    Hepatotoxicity has been reported with bortezomib use, including acute liver failure, hepatitis, elevated hepatic enzymes, and hyperbilirubinemia. Bortezomib should be initiated at a reduced dose in patients with moderate or severe hepatic disease; subsequent doses may be increased or decreased based on patient tolerability. Monitor hepatic enzymes during therapy. Hold bortezomib therapy to assess reversibility in patients who develop hepatotoxicity.

    Diabetes mellitus

    Patients with diabetes mellitus receiving oral antidiabetic agents and concurrent bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication. Both hyperglycemia and hypoglycemia have been reported in patients receiving bortezomib.

    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.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    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. These patients should use effective contraception during and after bortezomib therapy; additionally, male patients with a female partner of reproductive potential should use effective contraception during and after bortezomib therapy due to the risk of male-mediated teratogenicity. Women who become pregnant while receiving bortezomib should be apprised of the potential hazard to the fetus. Female patients of reproductive potential and male patients with a female partner of reproductive potential should use effective contraception during and for at least 2 months after the last dose of bortezomib. There is a risk of male or female infertility with bortezomib therapy based on its mechanism of action and data from animal studies.

    Breast-feeding

    No information is available regarding the presence of bortezomib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended during bortezomib therapy or for 2 months after the last dose.

    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 (unspecified) / 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
    cranial nerve palsies / Delayed / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    stroke / Early / Incidence not known
    coma / Early / Incidence not known
    leukoencephalopathy / Delayed / 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

    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

    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

    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.
    Acetaminophen; Butalbital: (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.
    Acetaminophen; 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.
    Acetaminophen; Butalbital; 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.
    Alogliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as alogliptin, and receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Alogliptin; Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as alogliptin, and receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Alogliptin; Pioglitazone: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as alogliptin, and receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    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: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents 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; Lansoprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors. (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.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors. (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.
    Amprenavir: (Moderate) Amprenavir may inhibit the metabolism and increase the serum concentrations of medications that are metabolized via cytochrome P450 3A4, including bortezomib.
    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.
    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; Butalbital; 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.
    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.
    Aspirin, ASA; Omeprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    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. (Minor) Plasma concentrations of bortezomib may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    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.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Belladonna Alkaloids; Ergotamine; 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.
    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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering bortezomib with boceprevir due to an increased potential for bortezomib-related adverse events. If bortezomib dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of bortezomib. Bortezomib is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated bortezomib plasma concentrations.
    Bosentan: (Moderate) If bortezomib is administered to a patient receiving antihypertensive agents, closely monitor the blood pressure and alter the antihypertensive dose, if needed, based on clinical response. Of note, coadminister bortezomib and bosentan carefully; bortezomib is a significant substrate for CYP3A4 and bosentan is a CYP3A4 inducer.
    Brigatinib: (Moderate) Monitor for decreased efficacy of bortezomib if coadministration with brigatinib is necessary. Bortezomib is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of bortezomib may decrease. Coadministration with a strong CYP3A4 inducer is expected to decrease the exposure of bortezomib by at least 45%; coadministration with a weak CYP3A4 inducer had no effect on the exposure of bortezomib.
    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.
    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.
    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: (Minor) Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations; medication dosage adjustment may be needed. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in patients with diabetes receiving oral hypoglycemics.
    Canagliflozin; Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations; medication dosage adjustment may be needed. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in patients with diabetes receiving oral hypoglycemics.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    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.
    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.
    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.
    Cisplatin: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like cisplatin; the risk of peripheral neuropathy may be additive.
    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: (Minor) Plasma concentrations of bortezomib may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Minor) Plasma concentrations of bortezomib may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Plasma concentrations of bortezomib may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
    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.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bortezomib, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bortezomib. Treatment with bortezomib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    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.
    Corticotropin, ACTH: (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.
    Dalfopristin; Quinupristin: (Minor) Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including bortezomib.
    Dapagliflozin: (Minor) Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations; medication dosage adjustment may be needed. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in patients with diabetes receiving oral hypoglycemics.
    Dapagliflozin; Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations; medication dosage adjustment may be needed. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in patients with diabetes receiving oral hypoglycemics.
    Dapagliflozin; Saxagliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications. (Minor) Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations; medication dosage adjustment may be needed. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in patients with diabetes receiving oral hypoglycemics.
    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) 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. (Minor) Plasma concentrations of bortezomib may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; 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.
    Dasatinib: (Major) Dasatinib may inhibit the CYP3A4 mediated metabolism of bortezomib. Increased adverse reactions from bortezomib may occur.
    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.
    Dexlansoprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    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.
    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.
    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.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    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: (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.
    Empagliflozin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Empagliflozin; Linagliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as linagliptin, receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Empagliflozin; Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    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.
    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.
    Erythromycin; Sulfisoxazole: (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.
    Esomeprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Esomeprazole; Naproxen: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    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.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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.
    Fluoxetine; Olanzapine: (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) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin.
    Glyburide; Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin.
    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: (Severe) 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; 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 (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.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrochlorothiazide, HCTZ; 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.
    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) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with bortezomib, a CYP3A substrate, as bortezomib toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    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: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    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: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like isoniazid; the risk of peripheral neuropathy may be additive.
    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. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like isoniazid; the risk of peripheral neuropathy may be additive.
    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. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like isoniazid; the risk of peripheral neuropathy may be additive.
    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%.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and bortezomib concurrently. Ivacaftor is an inhibitor of CYP3A and bortezomib is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bortezomib, can theoretically increase bortezomib exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: (Moderate) Ketoconazole inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity. Monitor for potential toxicity.
    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.
    Lansoprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Lansoprazole; Naproxen: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Linagliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as linagliptin, receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Linagliptin; Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as linagliptin, receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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. (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 lopinavir, 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.
    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%.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and bortezomib concurrently. Ivacaftor is an inhibitor of CYP3A and bortezomib is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bortezomib, can theoretically increase bortezomib exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Mephobarbital: (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.
    Metformin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin.
    Metformin; Pioglitazone: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin.
    Metformin; Repaglinide: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Metformin; Rosiglitazone: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin.
    Metformin; Saxagliptin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Metformin; Sitagliptin: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    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, RU-486: (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.
    Nateglinide: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    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; 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.
    Nevirapine: (Minor) Agents that induce cytochrome P450 3A4 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.
    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.
    Ombitasvir; Paritaprevir; 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.
    Omeprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Omeprazole; Sodium Bicarbonate: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    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.
    Oxcarbazepine: (Moderate) Oxcarbazepine induces cytochrome P450 3A4 and 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 oxcarbazepine is not known.
    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.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pantoprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    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.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    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.
    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: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral antidiabetic agents. Patients on antidiabetic agents 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.
    Proton pump inhibitors: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Rabeprazole: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Repaglinide: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Reserpine: (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.
    Ribociclib: (Minor) Use caution if coadministration of ribociclib, a moderate CYP3A4 inhibitor, with bortezomib, a CYP3A4 substrate is necessary. A strong inhibitor increased the exposure of bortezomib by 35%. Moderate inhibitors like ribociclib may also increase the serum concentration of bortezomib, although to a lesser extent. The clinical significance of this interaction is unknown.
    Ribociclib; Letrozole: (Minor) Use caution if coadministration of ribociclib, a moderate CYP3A4 inhibitor, with bortezomib, a CYP3A4 substrate is necessary. A strong inhibitor increased the exposure of bortezomib by 35%. Moderate inhibitors like ribociclib may also increase the serum concentration of bortezomib, although to a lesser extent. The clinical significance of this interaction is unknown.
    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: (Minor) Rifapentine induces hepatic isoenzymes CYP3A4. Drugs metabolized by CYP3A4, such as bortezomib, may require dosage adjustments when administered concurrently with rifapentine. The manufacturer warns that patients who are receiving bortezomib concurrently with CYP3A4 inducers should be closely monitored for potential loss of efficacy.
    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.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Saxagliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    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.
    Simeprevir: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of bortezomib, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of bortezomib, such as peripheral neuropathy, hematologic toxicities, and GI events.
    Simvastatin; Sitagliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sitagliptin: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    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.
    Streptogramins: (Minor) Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including bortezomib.
    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: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents 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.
    Tamoxifen: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering bortezomib with telaprevir due to an increased potential for bortezomib-related adverse events. If bortezomib dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of bortezomib. Bortezomib is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated bortezomib plasma concentrations.
    Telithromycin: (Minor) Concentrations of bortezomib may be increased with concomitant use of telithromycin. Bortezomib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and bortezomib is necessary, as the systemic exposure of bortezomib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of bortezomib; consider increasing the dose of bortezomib if necessary. Bortezomib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Co-administration of a strong CYP3A4 inducer decreased the exposure of bortezomib by at least 45% in a small drug interaction study (n = 6).
    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: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Thiopental: (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.
    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.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Vinblastine: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like vinblastine; the risk of peripheral neuropathy may be additive.
    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.
    Voriconazole: (Minor) Voriconazole inhibits cytochrome P450 3A4 and may increase the exposure to bortezomib and increase the risk for toxicity.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Zalcitabine, ddC: (Major) Avoid the concomitant use of bortezomib and zalcitabine; the risk of peripheral neuropathy may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of peripheral neuropathy.
    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.

    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. These patients should use effective contraception during and after bortezomib therapy; additionally, male patients with a female partner of reproductive potential should use effective contraception during and after bortezomib therapy due to the risk of male-mediated teratogenicity. Women who become pregnant while receiving bortezomib should be apprised of the potential hazard to the fetus. Female patients of reproductive potential and male patients with a female partner of reproductive potential should use effective contraception during and for at least 2 months after the last dose of bortezomib. There is a risk of male or female infertility with bortezomib therapy based on its mechanism of action and data from animal studies.

    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, I?B), 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 (NF)-?B through stabilization of the inhibitor protein I?B. Myeloma cells depend on the NF-?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-?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 (n = 14) or subcutaneously (n = 17) in multiple myeloma patients; the AUC geometric mean ratio was 0.99 (90% CI, 80.18% to 122.8%). The Cmax value was lower following subcutaneous administration compared with intravenous administration (20.4 ng/mL vs. 223 ng/mL).