Velcade

Bortezomib.

VELCADE (bortezomib) for Injection is an antineoplastic agent available for intravenous injection (IV) or subcutaneous (SC) use. Each single use vial contains: 1.0 mg (IV use only) or 3.5 mg (IV or SC use) as a sterile lyophilized powder.
Each vial is contained in a transparent blister pack consisting of a tray with a lid. The 5 ml vial contains 11 mg powder for solution for injection and the 10 ml vial contains 38.5 mg powder for solution for injection.
Excipients/Inactive Ingredients: Mannitol (E421)

Pharmacology: Pharmacodynamics: Mechanism of action: Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.
Clinical Trials: Phase 2 Clinical Studies in Relapsed Multiple Myeloma: The safety and efficacy of VELCADE IV were evaluated in an open-label, single-arm, multicenter study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy. The median number of prior therapies was six. Baseline patient and disease characteristics are summarized in Table 1.
An IV bolus injection of VELCADE 1.3 mg/m²/dose was administered twice weekly for 2 weeks, followed by a 10 day rest period (21 day treatment cycle) for a maximum of 8 treatment cycles. The study employed dose modifications for toxicity (see Dosage & Administration). Patients who experienced a response to VELCADE treatment were allowed to continue VELCADE treatment in an extension study. (See Table 1.)

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Responses to VELCADE alone are shown in Table 2. Response rates to VELCADE alone were determined by an independent review committee (IRC) based on criteria published by Bladé and others. Complete response required <5% plasma cells in the marrow, 100% reduction in M protein, and a negative immunofixation test (IF-). Response rates using the SWOG criteria are also shown. SWOG response required a ≥75% reduction in serum myeloma protein and/or ≥90% urine protein.3 A total of 188 patients were evaluated for response; 9 patients with nonmeasurable disease could not be evaluated for response by the IRC. Five patients were excluded from the efficacy analyses because they had minimal prior therapy.
Ninety-eight percent of study patients received a starting dose of 1.3 mg/m² administered IV. Twenty-eight percent of these patients received a dose of 1.3 mg/m² throughout the study, while 33% of patients who started at a dose of 1.3 mg/m² had to have their dose reduced during the study. Sixty-three percent of patients had at least one dose held during the study. In general, patients who had a confirmed CR received 2 additional cycles of VELCADE treatment beyond confirmation. It was recommended that responding patients receive up to 8 cycles of VELCADE therapy. The mean number of cycles administered was 6.
The median time to response was 38 days (range 30 to 127 days).
The median survival of all patients enrolled was 16 months (range <1 to 18+ months). (See Table 2.)

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In this study, the response rate to VELCADE was independent of the number and types of prior therapies. There was a decreased likelihood of response in patients with either >50% plasma cells or abnormal cytogenetics in the bone marrow. Responses were seen in patients with chromosome 13 abnormalities.
A small dose-response study (M34100-24) was performed in 54 patients with multiple myeloma who received a 1.0 mg/m²/dose or a 1.3 mg/m²/dose twice weekly for two out of three weeks. A single complete response was seen at each dose, and there were overall (CR + PR) response rates of 30% (8/27) at 1.0 mg/m² and 38% (10/26) at 1.3 mg/m².
Patients who did not obtain an optimal response to therapy with VELCADE alone (progressive or stable disease after 2 or 4 cycles, respectively) were able to receive high-dose dexamethasone in conjunction with VELCADE (i.e., 40 mg dexamethasone with each dose of VELCADE administered orally as 20 mg on the day of and 20 mg the day after VELCADE administration, (i.e., Days 1, 2, 4, 5, 8, 9, 11, and 12), thus 160 mg over 3 weeks). A total of 74 patients were administered dexamethasone in combination with VELCADE and were assessed for response. Eighteen percent (13/74) of patients achieved or had an improved response (CR 11% or PR 7%) with combination treatment.
Randomized, Open-Label Clinical Study in Relapsed Multiple Myeloma comparing VELCADE to Dexamethasone: A prospective phase 3, international, randomized (1:1), stratified, open-label clinical trial [M34101-039 (APEX)] enrolling 669 patients was designed to determine whether VELCADE resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline grade ≥2 peripheral neuropathy or platelet counts <50,000/µl. A total of 627 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had previously received (1 previous line versus more than 1 line of therapy), time of progression relative to prior treatment (progression during or within 6 months of stopping their most recent therapy versus relapse >6 months after receiving their most recent therapy), and screening β₂-microglobulin levels (≤ 2.5 mg/l versus >2.5 mg/l).
Baseline patient and disease characteristics are summarized in Table 3.

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Patients in the VELCADE treatment group were to receive eight 3-week treatment cycles followed by three 5-week treatment cycles of VELCADE. Within each 3-week treatment cycle, VELCADE 1.3 mg/m²/dose alone was administered by IV bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle, VELCADE 1.3 mg/m²/dose alone was administered by IV bolus once weekly for 4 weeks on Days 1, 8, 15, and 22 followed by a 13-day rest period (Days 23 to 35) (see Dosage & Administration).
Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles followed by five 4-week treatment cycles. Within each 5-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15-day rest period (Days 21 to -35). Within each 4-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered VELCADE at a standard dose and schedule on a companion study.
Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered VELCADE, regardless of disease status. At this time of study termination, a final statistical analysis was performed. Due to this early termination of the study, the median duration of follow-up for surviving patients (n=534) is limited to 8.3 months.
In the VELCADE arm, 34% of patients received at least 1 VELCADE dose in all 8 of the 3-week cycles of therapy, and 13% received at least 1 dose in all 11 cycles. The average number of VELCADE doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least 1 dose in all 4 of the 5-week treatment cycles of therapy, and 6% received at least 1 dose in all 9 cycles.
The time to event analyses and response rates from the phase 3 trial are presented in Table 4. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required <5% plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test (IF-). Partial Response (PR) requires ≥50% reduction in serum myeloma protein and ≥90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis, however M-protein was still detectable by immunofixation (IF⁺). (See Table 4.)

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Randomized, Open-Label Clinical Study in Relapsed Multiple Myeloma comparing VELCADE IV and SC: An open label, randomized, phase 3 non-inferiority study (MMY-3021) compared the efficacy and safety of the subcutaneous administration (SC) of VELCADE versus the intravenous administration (IV). This study included 222 patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m² of VELCADE by either the SC or IV route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with VELCADE alone after 4 cycles were allowed to receive dexamethasone 20 mg daily on the day of and after VELCADE administration. Patients with baseline grade ≥2 peripheral neuropathy or platelet counts <50,000/µL were excluded. A total of 218 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had received (1 previous line versus more than 1 line of therapy), and international staging system (ISS) stage (incorporating beta₂-microglobulin and albumin levels; Stages I, II, or III). Baseline patient and disease characteristics are summarized in Table 5.

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This study met its primary objective of non-inferiority for response rate (CR + PR) after 4 cycles of single agent VELCADE for both the SC and IV routes, 42% in both groups. In addition, secondary response-related and time to event related efficacy endpoints showed consistent results for SC and IV administration (see Table 6).

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Table 7 presents a cross-tabulation summary of best response by algorithm after 4 cycles versus after 8 cycles for patients who received dexamethasone. Eighty-two subjects in the SC treatment group and 39 subjects in the IV treatment group received dexamethasone after cycle 4.
Dexamethasone had a similar effect on improvement of response on both treatment arms: 30% (SC) and 30% (IV) of patients with no response at end of Cycle 4 obtained a response later.
13% (SC) and 13% (IV) of patients with PR at end of Cycle 4 obtained a CR later. (See Table 7.)

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Relative to previously reported outcomes, the ORR after 8 cycles of treatment (52% in both treatment groups) and time to progression (median 10.4 months and 9.4 months in SC and IV treatment groups, respectively), including the effect of the addition of dexamethasone from cycle 5 onwards, were higher than observed in prior registration study with single agent IV VELCADE (38% ORR and median TTP of 6.2 months for the VELCADE arm). Time to Progression and ORR was also higher compared to the subgroup of patients that received only 1 prior line of therapy (43% ORR and median TTP of 7.0 months) (see Table 4).
VELCADE Retreatment in Relapsed Multiple Myeloma: Study MMY-2036 (RETRIEVE) was an open label, multicenter study designed to determine the efficacy and safety of retreatment with VELCADE in 130 patients with relapsed multiple myeloma. Patients had previously tolerated 1.0 or 1.3 mg/m² VELCADE alone or in combination with other agents, had CR or PR upon completion of VELCADE therapy and subsequently relapsed.
As assessed by EBMT criteria, the primary endpoint of best response was achieved in 40% of patients who had a response of PR or better including 1% of whom had a best response of CR. In these 40% of patients (n=50) who had a best response of PR or better, the median time to progression (TTP) was 8.4 months (range: 3.3 to 20.7 months). The median duration of response in these patients was 6.5 months (range: 0.6 to 19.3 months).
VELCADE Combination Treatment with Pegylated Liposomal Doxorubicin: A Phase 3 randomized, parallel-group, open-label, multicentre study (DOXIL-MMY-3001) was conducted in 646 patients comparing the safety and efficacy of VELCADE plus pegylated liposomal doxorubicin combination therapy with VELCADE monotherapy in patients with multiple myeloma who had received at least 1 prior therapy and who did not progress while receiving anthracycline-based therapy. The primary efficacy endpoint was TTP while the secondary efficacy endpoints were OS and ORR (CR+PR), using the European Group for Blood and Marrow Transplantation (EBMT) criteria.
There was a significant improvement in the primary endpoint of time to progression (TTP) for patients treated with combination therapy of VELCADE and pegylated liposomal doxorubicin. A protocol-defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI; 29-57%), p<0.0001. The median TTP was 6.5 months for the VELCADE monotherapy patients compared with 9.3 months for the VELCADE plus pegylated liposomal doxorubicin combination therapy patients. These results, though not mature, constituted the protocol defined final analysis.
VELCADE Combination Treatment with Dexamethasone: Study MMY-2045 was a Phase 2 randomised open-label study to evaluate VELCADE in combination with dexamethasone (Vc+Dex) followed by either Vc+Dex or Vc+Dex in combination with cyclophosphamide (VDC), or lenalidomide (VDL). 163 patients with relapsed/progressive or refractory multiple myeloma were enrolled. The primary efficacy endpoint was the ORR. Secondary endpoints were changes in renal function after 4 cycles of Vc+Dex treatment, time to response, TTP, duration of response, PFS, 1-year survival, and OS.
The key efficacy results in 144 patients who received the VELCADE plus dexamethasone combination are presented in Table 8. The results demonstrate incremental benefit when compared to the previous, well-controlled VELCADE monotherapy study (APEX) and a positive effect of the combination of Vc+Dex on response rates, TTP, time to first response, PFS, and 1-year survival rate. The results are also consistent with Study MMY-3021 in which an improvement in response was seen when dexamethasone was added to VELCADE treatment in multiple myeloma patients after 4 cycles. (See Table 8.)

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Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma: A prospective phase 3, international, randomized (1:1), open-label clinical study [MMY-3002 (VISTA)] of 682 patients was conducted to determine whether VELCADE (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m²) and prednisone (60 mg/m²) in patients with previously untreated multiple myeloma. This study included patients who were not candidates for stem-cell transplant. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Baseline demographics and patient characteristics are summarized in Table 9.

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At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and patients in the MP arm were offered VcMP treatment. Median follow-up was 16.3 months. The final survival update was performed with a median duration of follow-up at 60.1 months. A statistically significant survival benefit in favor of the VcMP treatment group was observed (HR=0.695; p=0.00043) despite subsequent therapies that included VELCADE based regimens. The median survival in MP treatment group has been estimated at 43.1 months, and the median survival on the VcMP treatment group has been estimated at 56.4 months . Efficacy results are presented in Table 10.

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Previously Untreated Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation: An integrated data analysis was conducted of three phase 3 trials (MMY-3003, IFM-2005-01, MMY-3010) to demonstrate the safety and efficacy of VELCADE, as induction therapy prior to stem cell transplantation in patients with previously untreated multiple myeloma. These studies were similar in design (randomized, open-label, multicenter) and included 1572 patients (men and women up to 65 years of age with previously untreated multiple myeloma [Durie-Salmon stage II or III] and ECOG PS of 0 to 2/3). Patients received either a VELCADE-containing induction regimen (n=787) or a non-VELCADE-containing induction regimen (n=785). These studies evaluated VELCADE in combination with: 1) dexamethasone and adriamycin (MMY-3003), 2) thalidomide and dexamethasone (MMY-3010), or 3) dexamethasone alone (IFM-2005-01). VELCADE-containing induction regimens were compared to regimens including vincristine, adriamycin and dexamethasone or thalidomide and dexamethasone.
The VELCADE-based treatment group had improved PFS and TTP compared with the non-VELCADE-based treatment group. In addition, patients who received a VELCADE-containing induction regimen had improved post transplant and post induction response rates compared to those who received a non-VELCADE-containing induction regimen.
Integrated efficacy results from studies MMY-3003, IFM-2005-01, MMY-3010 are summarized in the following table: See table 11.

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A fourth phase 3 randomized, open-label, multicenter trial (MMY-3006) was conducted in 480 patients (men and women aged 18 to 65 years of age with previously untreated multiple myeloma).⁴ In this study, VELCADE-containing induction regimens were compared to regimens containing thalidomide and dexamethasone. The results of this study were consistent with those of the integrated analysis demonstrating improved post–induction CR+nCR rates (31% versus 11% ; p<0.0001), post-transplant CR+nCR rates (55% versus 41%; p=0.0025), and a 37% reduction in the risk of disease progression or death (HR = 0.63 [95% CI: 0.45, 0.88]; p=0.0061) with the VELCADE-based induction regimen as compared with its non-VELCADE-based comparator regimen. The safety profile in the VELCADE-containing regimen was consistent with the known safety profile of VELCADE.
A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior therapy: The safety and efficacy of VELCADE in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study [M34103-053 (PINNACLE)] of 155 patients with progressive disease who had received at least 1 prior therapy. VELCADE was administered at the recommended dose of 1.3 mg/m². The median number of cycles administered across all patients was 4 (range 1-17); and 8 in responding patients. Response rates to VELCADE are described in Table 12.

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With a median duration of follow up of more than 13 months in surviving patients, the median survival had not yet been reached and the Kaplan Meier estimate of 1-year survival was 69%. The Kaplan-Meier estimate of 1-year survival was 94% in responders and 100% in those achieving CR or CRu.
Previously Untreated Mantle Cell Lymphoma: A randomized, open-label, Phase 3 study (LYM-3002) was conducted in 487 adult patients with previously untreated mantle cell lymphoma (Stage II, III or IV) to determine whether VELCADE administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) resulted in improvement in progression free survival (PFS) when compared to the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This clinical study utilized independent pathology confirmation and independent radiologic response assessment.
Patients in the VcR-CAP treatment arm received VELCADE (1.3 mg/m²) administered intravenously on Days 1, 4, 8, and 11 (rest period Days 12-21); rituximab (375 mg/m²) on Day 1; cyclophosphamide (750 mg/m²) on Day 1; doxorubicin (50 mg/m2) on Day 1; and prednisone (100 mg/m²) on Day 1 through Day 5 of the 21-day treatment cycle. For patients with a response first documented at Cycle 6, two additional treatment cycles were given.
Median patient age was 66 years, 74% were male, 66% were Caucasian and 32% were Asian. 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 35% of patients had an International Prognostic Index (IPI) score of 3 (high-intermediate) and 74% had Stage IV disease. Median number of cycles received by patients in both treatment arms was 6 with 17% of patients in the R-CHOP group and 14% of subjects in the VcR-CAP group receiving up to 2 additional cycles. The majority of the patients in both groups received 6 or more cycles of treatment, 83% in the R-CHOP group and 84% in the VcR-CAP group.
The primary efficacy endpoint was progression-free survival based on Independent Review Committee (IRC) assessment. Secondary endpoints included, time to progression (TTP), time to next anti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response rate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration. The response criteria used to assess efficacy were based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma (IWRC)⁶.
A 59% improvement in the primary endpoint of PFS (Hazard Ratio [HR]=0.63; p<0.001) was observed in the VcR-CAP group (median=24.7 months) as compared to the R-CHOP group (median=14.4 months). A statistically significant benefit in favor of the VcR-CAP treatment group was observed for TTP, TNT, TFI and the overall complete response rate. The median duration of complete response was more than double in the VcR-CAP group (42.1 months) compared with the R-CHOP group (18 months) and the duration of overall response was 21.4 months longer in the VcR-CAP group. With a median duration of follow-up of 40 months, median OS (56.3 months in the R-CHOP group, and not reached in the VcR CAP group) favored the VcR-CAP group, (estimated HR=0.80; p=0.173). There was a trend towards prolonged overall survival favoring the VcR-CAP group; the estimated 4-year survival rate was 53.9% in the R-CHOP group and 64.4% in the VcR-CAP group. Efficacy results at a median follow-up of 40 months are presented in Table 13.

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Patients with previously treated light-chain (AL) Amyloidosis: A Phase 1/2 study was conducted to determine the safety and efficacy of VELCADE in patients with previously treated light-chain (AL) Amyloidosis. No new safety concerns were observed during the study, and in particular VELCADE did not exacerbate target organ damage (heart, kidney and liver). In 49 evaluable patients treated at 1.6 mg/m² weekly or 1.3 mg/m² twice-weekly, a 67.3% response rate (including a 28.6% CR rate) as measured by haematological response (M- protein) was reported. For these dose cohorts, the combined 1 year survival rate was 88.1%.
Pediatric Use: The safety and effectiveness of VELCADE in pediatric patients has not been established.
Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; in the patients studied with multiple myeloma and mantle cell lymphoma, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetics: Following intravenous bolus administration of a 1.0 mg/m² and 1.3 mg/m² dose to eleven patients with multiple myeloma, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/ml respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the 1.0 mg/m² dose and 89 to 120 ng/ml for the 1.3 mg/m² dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40-193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 l/h following subsequent doses for doses of 1.0 mg/m² and 1.3 mg/m², respectively.
In the PK/PD substudy in Phase 3 trial, following an IV bolus or subcutaneous (SC) injection of a 1.3 mg/m² dose to multiple myeloma patients (n=14 for IV, n=17 for SC), the total systemic exposure after repeat dose administration (AUC_last) was equivalent for SC and IV administration. The C_max after SC administration (20.4 ng/mL) was lower than IV (223 ng/mL). The AUC_last geometric mean ratio was 0.99 and 90% confidence intervals were 80.18%-122.80%.
Distribution: The mean distribution volume of bortezomib ranged from 1659 liters to 3294 liters (489 to 1884 l/m²) single- or repeat-dose IV administration of 1.0 mg/m² or 1.3 mg/m² to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100-1000 ng/ml.
Metabolism: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after IV dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
Elimination: The pathways of elimination of bortezomib have not been characterized in humans.
Special Populations: Age, Gender, and Race: The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3 mg/m² doses to 104 pediatric patients (2-16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area (BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/m², volume of distribution at steady-state was 834 (39%) L/m², and the elimination half-life was 100 (44%) hours. After correcting for the BSA effect, other demographics such as age, body weight and sex did not have clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.
The effects of gender and race on the pharmacokinetics of bortezomib have not been evaluated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of IV bortezomib was assessed in 60 cancer patients at bortezomib doses ranging from 0.5 to 1.3 mg/m². When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely (see Table 18).
Renal Impairment: A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥60 ml/min/1.73 m², n=12), Mild (CrCL= 40-59 ml/min/1.73 m², n=10), Moderate (CrCL=20-39 ml/min/1.73 m², n=9), and Severe (CrCL <20 ml/min/1.73 m², n=3). A group of dialysis patients who were dosed after dialysis was also included in the study (n=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m² of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and C_max) was comparable among all the groups (see Dosage & Administration).
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥0.3 mg/m² (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m². VELCADE could have a potential effect on either male or female fertility.

VELCADE (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.
VELCADE (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma.

VELCADE may be administered: Intravenously (at a concentration of 1 mg/mL) as a 3 to 5 second bolus injection or; Subcutaneously (at a concentration of 2.5 mg/mL).
Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
At least 72 hours should elapse between consecutive doses of VELCADE.
VELCADE IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY. Intrathecal administration has resulted in death.
VELCADE retreatment may be considered for multiple myeloma patients who had previously responded to treatment with VELCADE (see discussion as follows, and Pharmacology: Pharmacodynamics under Actions).
Monotherapy: Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma: Recommended Dosage: The recommended dose of VELCADE is 1.3 mg/m²/dose administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). For extended therapy of more than 8 cycles, VELCADE may be administered on the standard schedule or, for relapse multiple myeloma, on maintenance schedule of once weekly for 4 weeks (days 1, 8, 15, and 22) followed by a 13-day rest period (days 23 to 35). At least 72 hours should elapse between consecutive doses of VELCADE.
Dose Modification and Reinitiation of Therapy: VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed as follows (see Precautions). Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1.0 mg/m²/dose; 1.0 mg/m²/dose reduced to 0.7 mg/m²/dose).
The following table contains the recommended dose modification for the management of patients who experience VELCADE-related neuropathic pain and/or peripheral sensory neuropathy (see Table 14). Severe autonomic neuropathy resulting in treatment interruption or discontinuation has been reported. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk/benefit assessment. (See Table 14.)

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Administration: VELCADE is administered intravenously or subcutaneously. When administered intravenously, VELCADE is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0.9% sodium chloride solution for injection. For subcutaneous administration, the reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injection sites should be rotated for successive injections.
If local injection site reactions occur following VELCADE injection subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously, or changed to IV injection.
Combination Therapy: Previously Untreated Multiple Myeloma-Patients who are Not Eligible for Stem Cell Transplantation: Recommended Dosage in Combination with Melphalan and Prednisone: VELCADE (bortezomib) for Injection is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 15. In Cycles 1-4, VELCADE is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is administered once weekly (days 1, 8, 22 and 29). (See Table 15.)

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Dose Management Guidelines for Combination Therapy with Melphalan and Prednisone: Dose modification and re-initiation of therapy when VELCADE is administered in combination with melphalan and prednisone.
Prior to initiating a new cycle of therapy: Platelet count should be ≥ 70 x 10⁹/l and the ANC should be ≥ 1.0 x 10⁹/l; Non-hematological toxicities should have resolved to Grade 1 or baseline. (See Table 16.)

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For additional information concerning melphalan and prednisone, see manufacturer's prescribing information.
Previously Untreated Multiple Myeloma-Patients who are Eligible for Stem Cell Transplantation: Recommended Dosage: The recommended starting dose of VELCADE in combination with other medicinal products used for the treatment of multiple myeloma is 1.3 mg/m² to be administered twice weekly on Days 1, 4, 8, and 11, followed by a rest period of 10-18 days, which is considered a treatment cycle. Three to 6 cycles should be administered. At least 72 hours should elapse between consecutive doses of VELCADE.
For VELCADE dosage adjustments for transplant eligible patients follow dose modification guidelines described previously under monotherapy (Table 14).
For dosing instructions for other medicinal products combined with VELCADE, see manufacturer's prescribing information.
Relapsed Multiple Myeloma: Recommended Dosage in Combination with Pegylated Liposomal-Doxorubicin: For VELCADE dosage and dose modifications, see previous discussion on Monotherapy.
Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the VELCADE 3 week regimen as a 1 hour intravenous infusion administered after the VELCADE injection.
For additional information concerning pegylated liposomal-doxorubicin, see manufacturer's prescribing information.
Recommended Dosage in Combination with Dexamethasone: For VELCADE dosage and dose modifications, see previous discussion on Monotherapy.
Dexamethasone is administered orally at 20 mg on the day of, and the day after, VELCADE administration.
For additional information concerning dexamethasone, see manufacturer's prescribing information.
Retreatment for Multiple Myeloma: Patients who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed should be started on retreatment at the last tolerated dose. Refer to Monotherapy for dosing schedule.
Previously Untreated Mantle Cell Lymphoma: Recommended Dosage in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone: For VELCADE dosage, see Monotherapy. Six VELCADE cycles are administered. For patients with a response first documented at Cycle 6, two additional VELCADE cycles are recommended.
The following medicinal products are administered on Day 1 of each VELCADE 3 week treatment cycle as intravenous infusions: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², and doxorubicin at 50 mg/m². Prednisone is administered orally at 100 mg/m² on Days 1, 2, 3, 4 and 5 of each treatment cycle.
Dose Adjustments during Treatment for Patients with Previously Untreated Mantle Cell Lymphoma: Prior to the first day of each cycle (other than Cycle 1): Platelet count should be ≥100 x 10⁹/L and absolute neutrophil count (ANC) should be ≥1.5 x 10⁹/L; Hemoglobin should be ≥8 g/dL (≥4.96 mmol/L); Non-hematologic toxicity should have recovered to Grade 1 or baseline.
VELCADE treatment must be withheld at the onset of any Grade 3 non hematological or Grade 3 hematological toxicities, excluding neuropathy (see Precautions). For dose adjustments, see Table 17.

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For dosing instructions for rituximab, cyclophosphamide, doxorubicin, or prednisone, see manufacturer's prescribing information.
Special Populations: Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure (see Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic Impairment: Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended VELCADE dose. For patients with moderate or severe hepatic impairment, see Table 18 (see also Pharmacology: Pharmacokinetics under Actions).

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Cardiovascular safety pharmacology studies in monkeys and dogs show that IV doses approximately two to three times the recommended clinical dose on a mg/m² basis are associated with increases in heart rate, decreases in contractility, hypotension and death. The decreased cardiac contractility and hypotension responded to acute intervention with positive inotropic or pressor agents. In dog studies, a slight increase in the corrected QT interval was observed at a lethal dose.
Overdosage more than twice the recommended dose in patients has been associated in patients with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes.
There is no known specific antidote for VELCADE overdosage. In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see Precautions and Dosage & Administration).

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron or mannitol.

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE is for IV and subcutaneous use only. DO NOT ADMINISTER VELCADE INTRATHECALLY.
Overall, the safety profile of patients treated with VELCADE in monotherapy was similar to that observed in patients treated with VELCADE in combination with melphalan and prednisone.
Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy (PN) that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported.
Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 study comparing VELCADE IV vs SC the incidence of Grade ≥2 peripheral neuropathy events was 24% for SC and 41% for IV (p=0.0124). Grade ≥3 peripheral neuropathy occurred in 6% of subjects in the SC treatment group, compared with 16% in the IV treatment group (p=0.0264) (see Table 22). Therefore, patients with pre-existing PN or at high risk of peripheral neuropathy may benefit from starting VELCADE subcutaneously.
Patients experiencing new or worsening peripheral neuropathy may require a change in dose, schedule or route of administration to SC (see Dosage & Administration). Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the single agent phase 3 multiple myeloma study of VELCADE vs dexamethasone. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies.
The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
Hypotension: In phase 2 and 3 single agent multiple myeloma studies, the incidence of hypotension (postural, orthostatic, and Hypotension Not Otherwise Specified) was 11% to 12%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids and/or sympathomimetics (see Adverse Reactions).
Cardiac Disorders: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the single agent phase 3 multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively.
There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Hepatic Events: Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.
Pulmonary Disorders: There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. In the event of new or worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and patients treated appropriately.
In a clinical trial, two patients given high-dose cytarabine (2 g/m² per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
Laboratory Tests: Complete blood counts (CBC) should be frequently monitored throughout treatment with VELCADE.
Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia (see Adverse Reactions). Platelets were lowest at Day 11 of each cycle of VELCADE treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet count decrease and recovery remain consistent in the 8 studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in any of the regimens studied.
Platelet counts should be monitored prior to each dose of VELCADE. VELCADE therapy should be held when the platelet count is <25,000/uL (see Dosage & Administration and Adverse Reactions). There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusion and supportive care may be considered.
In the single-agent multiple myeloma study of VELCADE vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pre-treatment platelet count is shown in Table 19. The incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. (See Table 19.)

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In the combination study of VELCADE with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia adverse events (≥Grade 4) was 32% versus 2% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm. The incidence of bleeding adverse events (≥Grade 3) was 1.7% (4 patients) in the VcR-CAP arm and was 1.2% (3 patients) in the R-CHOP arm.
There were no deaths due to bleeding events in either arm. There were no CNS bleeding events in the VcR-CAP arm; there was 1 bleeding event in the R-CHOP arm. Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm.
The incidence of neutropenia (≥Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Colony-stimulating factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm.
Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting (see Adverse Reactions) sometimes requiring use of antiemetics and antidiarrheal medications. Fluid and electrolyte replacement should be administered to prevent dehydration. Since patients receiving VELCADE therapy may experience vomiting and/or diarrhea, patients should be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.
Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells the complications of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Patients with Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. See Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.
Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.
Effects on ability to drive and use machines: VELCADE may cause tiredness, dizziness, fainting, or blurred vision. Patients should be advised not to drive or operate machinery if they experience these symptoms.

Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested [0.075 mg/kg (0.5 mg/m²) in the rat and 0.05 mg/kg (0.6 mg/m²) in the rabbit] when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m² based on body surface area.
Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/m²) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/m² based on body surface area.
No placental transfer studies have been conducted with bortezomib. There are no adequate and well-controlled studies in pregnant women. If VELCADE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breast feeding during treatment with VELCADE.
Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, women should be advised against breast feeding while being treated with VELCADE.

Summary of Clinical Trials of VELCADE IV in Patients with Relapsed/Refractory Multiple Myeloma: The safety and efficacy of VELCADE were evaluated in 3 studies at the recommended dose of 1.3 mg/m². These included a phase 3 randomized, comparative study, versus dexamethasone of 669 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy (M34101-039); a phase 2 single arm, open-label, multicenter study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy (M34100-025); and a phase 2 dose-response clinical study in relapsed multiple myeloma for patients who had progressed or relapsed on or after first line therapy with VELCADE 1.0 mg/m² or 1.3 mg/m² (M34100-024). (See Table 20.)

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Summary of Clinical Trials of VELCADE IV vs SC in Patients with Relapsed Multiple Myeloma: The safety and efficacy of VELCADE SC were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m². This was a randomized, comparative study of VELCADE IV vs SC in 222 patients with relapsed multiple myeloma. (See Table 21.)

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Although, in general safety data were similar for the IV and SC treatment groups, the following table highlights differences larger than 10% in the overall incidence of adverse drug reactions between the two treatment arms. (See Table 22.)

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Patients who received VELCADE subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment emergent adverse drug reactions that were grade 3 or higher in toxicity (57% vs 70% respectively), and a 5% lower incidence of discontinuation of VELCADE (22% vs 27%). The overall incidence of diarrhea (24% for the SC arm vs 36% for the IV arm), gastrointestinal and abdominal pain (6% for the SC arm vs 19% for the IV arm), asthenic conditions (27% for SC arm vs 39% for IV arm), upper respiratory tract infections (14% SC arm vs 26% IV arm) and peripheral neuropathy NEC (38% SC arm vs 53% IV arm) were 12%-15% lower in the subcutaneous group than the intravenous group. In addition, the incidence of peripheral neuropathies that were grade 3 or higher in toxicity was 10% lower (6% for SC vs 16% for IV), and the discontinuation rate due to peripheral neuropathies was 8% lower for the subcutaneous group (5%) as compared to the intravenous group (12%).
Six percent of patients were reported to have had an adverse local reaction to SC administration, mostly redness. Only 2 (1%) subjects were reported as having severe reactions. These severe local reactions were 1 case of pruritus and 1 case of redness. These reactions seldom led to dose modifications and all resolved in a median of 6 days.
VELCADE Retreatment in Relapsed Multiple Myeloma: The following table describes adverse drug reactions reported for at least 10% of patients with relapsed multiple myeloma who received retreatment with VELCADE IV (Study MMY-2036). (See Table 23.)

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Summary of Clinical Trials of VELCADE Combination Therapy in Patients with Relapsed Multiple Myeloma: The following table describe adverse drug reactions reported for at least 10% of patients with relapsed multiple myeloma who received VELCADE in combination with dexamethasone (Study MMY-2045) or VELCADE in combination with pegylated liposomal doxorubicin (Study DOXIL-MMY-3001). (See Table 24.)

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Summary of Clinical Trials in patients with previously untreated multiple myeloma: The following table describes safety data from 340 patients with previously untreated multiple myeloma who received VELCADE IV (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) in a prospective phase 3 study. (See Table 25.)

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Herpes zoster virus reactivation: Physicians should consider using antiviral prophylaxis in patients being treated with VELCADE. In the phase 3 study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with VcMP compared with MP (14% vs 4% respectively). Antiviral prophylaxis was administered to 26% of the patients in the VcMP arm. The incidence of herpes zoster among patients in the VcMP treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
The following table describes adverse drug reactions considered by the Company to have at least a possible causal relationship to VELCADE from patients with previously untreated multiple myeloma eligible for stem cell transplantation who received VELCADE IV (1.3 mg/m²). 410 patients were treated with VELCADE in combination with doxorubicin and dexamethasone compared with 411 patients treated with vincristine, doxorubicin and dexamethasone in Study MMY-3003, 239 were treated with VELCADE in combination with dexamethasone alone compared with 239 patients treated with vincristine, doxorubicin and dexamethasone in Study IFM 2005-01, and 130 were treated with VELCADE in combination with thalidomide and dexamethasone compared with 126 patients treated with thalidomide and dexamethasone in Study MMY-3010. For these 3 studies conducted in the transplant setting (MMY3003, IFM2005-01, MMY3010), only the adverse reactions during the induction phase of treatment are considered for the table. (See Table 26.)

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Summary of the Clinical Trial in Patients with Relapsed Mantle Cell Lymphoma: Safety data for patients with relapsed mantle cell lymphoma were evaluated in a phase 2 study [M34103-053 (PINNACLE)], which included 155 patients treated with VELCADE at the recommended dose of 1.3 mg/m². The safety profile of VELCADE in these patients was similar to that observed in patients with multiple myeloma. Notable differences between the two patient populations were that thrombocytopenia, neutropenia, anemia, nausea, vomiting and pyrexia were reported more often in the patients with multiple myeloma than in those with mantle cell lymphoma; whereas peripheral neuropathy, rash and pruritis were higher among patients with mantle cell lymphoma compared to patients with multiple myeloma.
Summary of Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma: Table 27 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received VELCADE (1.3 mg/m²) administered IV in combination with rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and prednisone (100 mg/m²) (VcR-CAP) in a prospective randomized study.
The incidences of Grade ≥3 bleeding events were similar between the 2 arms (3 patients in the VcR-CAP arm and 1 patient in the R-CHOP arm). All of the Grade ≥3 bleeding events resolved without sequelae in the VcR-CAP arm.
Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the R-CHOP arm. Respiratory tract and lung infections were reported, with the predominant preferred term of pneumonia (VcR-CAP 8% versus R CHOP 5%).
The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0. 8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment. (See Table 27.)

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Post-Marketing Experience: Clinically significant adverse drug reactions are listed here if they have not been reported previously.
The frequencies provided as follows reflect reporting rates of adverse drug reactions from the worldwide post-marketing experience with VELCADE. The frequencies provided as follows reflect reporting rates and precise estimates of incidence cannot be made. These adverse drug reactions are ranked by frequency, using the following convention: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000 including isolated reports). (See Table 28.)

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In vitro and animal ex vivo studies indicate that bortezomib is a weak inhibitor of cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is not expected to affect the overall disposition of bortezomib.
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of VELCADE, showed a bortezomib AUC mean increase of 35%, based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir).
In a drug-drug interaction study assessing the effect of omeprazole, a potent inhibitor of CYP2C19, on the pharmacokinetics of VELCADE there was no significant effect on the pharmacokinetics of bortezomib, based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of VELCADE showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. The concomitant use of VELCADE with strong CYP3A4 inducers is therefore not recommended, as efficacy may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort. In the same drug-drug interaction study, the effect of dexamethasone, a weaker CYP3A4 inducer was assessed. There was no significant effect on bortezomib pharmacokinetics based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on VELCADE showed a 17% increase in mean bortezomib AUC based on data from 21 patients. This is not considered clinically relevant.
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Patients should be cautioned about the use of concomitant medications that may be associated with peripheral neuropathy (such as amiodarone, anti-virals, isoniazid, nitrofurantoin, or statins), or with a decrease in blood pressure.
Drug Laboratory Test Interactions: None known.

Instructions for Use, Handling and Disposal: Administration Precautions: VELCADE is an antineoplastic. Caution should be used during handling and preparation. Proper aseptic technique should be used. Use of gloves and other protective clothing to prevent skin contact is recommended. In clinical trials, local skin irritation was reported in 5% of patients, but extravasation of VELCADE was not associated with tissue damage.
When administered subcutaneously, alternate sites for each injection (thigh or abdomen). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE is for IV and subcutaneous use only. DO NOT ADMINISTER VELCADE INTRATHECALLY.
Reconstitution/Preparation for Intravenous Administration: The contents of each vial should be reconstituted only with normal (0.9%) saline according to the following instructions based on route of administration: see Table 29.

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The reconstituted product should be a clear and colorless solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Procedure for Proper Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This product must not be mixed with other medicinal products except those mentioned in Instructions for Use, Handling and Disposal.

VELCADE contains no antimicrobial preservative. When reconstituted as directed, VELCADE may be stored at 25ºC (77ºF). Reconstituted VELCADE should be administered within 8 hours of preparation. The reconstituted material may be stored for up to 8 hours in the original vial or in a syringe. The total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
Do not store unopened vials above 30°C (86°F). Retain in original package to protect from light.
Shelf-Life: Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light.

Targeted Cancer Therapy

L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

POM

Powd for soln for inj (vial) (sterile, lyophilized, white to off-white cake or powder) 1.0 mg x 1's.